Piperidine derivatives

ABSTRACT

Piperidine derivatives of which the following is exemplary 
                         
and their use in the treatment of obesity, diabetes or dyslipidemia.

FIELD OF THE INVENTION

This invention relates to new compounds, in particular piperidinederivatives, to processes for preparing such compounds, to their use asinhibitors of acetyl-CoA carboxylase(s), to methods for theirtherapeutic use, in particular in diseases and conditions mediated bythe inhibition of acetyl-CoA carboxylase(s), and to pharmaceuticalcompositions comprising them.

BACKGROUND OF THE INVENTION

Obesity is a major public health issue not only for the EU, USA, Japanbut also for the world in general. It is associated with a number ofserious diseases including diabetes, dyslipidemia, hypertension,cardiovascular and cerebrovascular diseases. Although the underlyingmechanisms are not yet fully understood, the impairement of insulinaction in target tissues by accumulation of excess lipids is generallyregarded as a key mechanism linking obesity to secondary pathologies (G.Wolf, Nutrition Reviews Vol. 66(10):597-600; D B Savage, K F Petersen, GI Shulman, Physiol Rev. 2007; 87:507-520). Therefore, understanding ofcellular lipid metabolism in insulin target tissues is crucial in orderto elucidate the development of diseases associated with obesity.

A central event in lipid metabolism is the generation of malonyl-CoA viacarboxylation of acetyl-CoA by the two mammalian ACC isoforms ACC1(ACC-alpha, also termed ACCA) and ACC2 (ACC-beta, also designated ACCB)(Saggerson D. Annu Rev Nutr. 2008; 28:253-72). The malonyl-CoA generatedis used for de novo fatty acid synthesis and acts as inhibitor of CPT-1,thereby regulating mitochondrial fatty acid oxidation. Furthermore,malonyl-CoA is also described to act centrally to control food intake,and may play an important role in controlling insulin secretion from thepancreas (G D Lopaschuk, J R Ussher, J S Jaswal. Pharmacol Rev. 2010;62(2):237-64; D Saggerson Annu Rev Nutr. 2008; 28:253-72), furthercoordinating the regulation of intermediary metabolism.

Therefore ACC1 and ACC2 have been shown to be major regulators of fattyacid metabolism and are presently considered as an attractive target toregulate the human diseases of obesity, diabetes and cardiovascularcomplications (S J Wakil and L A Abu-Elheiga, J. Lipid Res. 2009. 50:S138-S143; L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry99:1476-1488, 2006).

As a result of its unique position in intermediary metabolism,inhibition of ACC offers the ability to inhibit de novo fatty acidproduction in lipogenic tissues (liver and adipose) while at the sametime stimulating fatty acid oxidation in oxidative tissues (liver,heart, and skeletal muscle) and therefore offers an attractive modalityfor favorably affecting, in a concerted manner, a multitude ofcardiovascular risk factors associated with obesity, diabetes, insulinresistance, nonalcoholic steatohepatitis (NASH) and the metabolicsyndrome (L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry99:1476-1488, 2006; Corbett J W, Harwood J H Jr., Recent Pat CardiovascDrug Discov. 2007 November; 2(3):162-80).

Furthermore recent data show that cellular toxicity mediated by lipids(lipotoxicity) is implicated in the susceptibitlity to diabetesassociated nephropathy (for review see M Murea, B I Freedmann, J SParks, P A Antinozzi, S C Elbein, L M Ma; Clin J Am Soc Nephrol. 2010;5:2373-9). A large-scale genome-wide association study in japanesepatients identified single nucleotide polymorphism in the ACC2 gene(ACACB) associated with diabetic nephropathy risk which was replicatedin nine independent cohorts. In the kidney, dysregulation of fatty acidmetabolism leading to increased fatty acid levels is believed to lead toglomerular and tubular dysfunction (M Murea, B I Freedmann, J S Parks, PA Antinozzi, S C Elbein, L M Ma; Clin J Am Soc Nephrol. 2010; 5:2373-9).Therefore inhibitors targeting ACC as key molecule involved in lipidoxidation have the potential to be beneficial for favorably affectingdiabetic nephropathy.

Additionally, insulin resistance, deregulated lipid metabolism,lipotoxicity and increased intramuscular lipids have also been describedto play a role in type 1 diabetes (I E Schauer, J K Snell-Bergeon, B CBergman, D M Maahs, A Kretowski, R H Eckel, M Rewers Diabetes 2011;60:306-14; P Ebeling, B Essen-Gustaysson, J A Tuominen and V A KoivistoDiabetologia 41: 111-115; K J Nadeau, J G Regensteiner, T A Bauer, M SBrown, J L Dorosz, A Hull, P Zeitler, B Draznin, JEB. Reusch J ClinEndocrinol Metab, 2010, 95:513-521). Therefore ACC inhibitors are alsoconsidered as interesting drugs for the treatment of type 1 diabetes.

In addition ACC inhibitors also have the potential to intervene in theprogression of diseases that result from the rapid growth of malignantcells or invading organisms that are dependent on endogenous lipidsynthesis to sustain their rapid proliferation. De novo lipogenesis isknown to be required for growth of many tumor cells and ACCup-regulation has been recognized in multiple human cancers, promotinglipogenesis to meet the need of cancer cells for rapid growth andproliferation (C Wang, S Rajput, K Watabe, D F Liao, D Cao Front Biosci2010; 2:515-26). This is further demonstrated in studies using ACCinhibitors which induced growth arrest and selective cytotoxicity incancer cells and by RNA interference-mediated knock-down of ACC whichinhibited growth and induced apoptosis in different types of cancercells. Furthermore, ACC1 associates with and is regulated by the breastcancer susceptibility gene 1 (BRCA1). Commonly occurring BRCA1 mutationslead to ACC1 activation and breast cancer susceptibility (C Wang, SRajput, K Watabe, D F Liao, D Cao Front Biosci 2010; 2:515-26).

Furthermore in central nervous system disorders including but notlimited to Alzheimer's disease, Parkinson disease and epilepsy,impairements in neuronal energy metabolism have been described (Ogawa M,Fukuyama H, Ouchi Y, Yamauchi H, Kimura J, J Neurol Sci. 1996;139(1):78-82). Interventions targeting this metabolic defect may provebeneficial to the patients. One promising intervention is therefore toprovide the glucose-compromised neuronscerebral brain neurons withketone bodies as an alternative substrate (ST HendersonNeurotherapeutics, 2008, 5:470-480; L C Costantini, L J Barr, J L Vogel,S T Henderson BMC Neurosci. 2008, 9 Suppl 2:S16; K W Baranano, A LHartman. Curr Treat Options Neurol. 2008; 10:410-9). ACC inhibitionleading to increased fatty acid oxidation may thereby result inincreases in the blood levels of ketone bodies thereby providing analternative energy substrate for the brain.

Preclinical and clinical evidence indicates that ketone bodies canprovide neuroprotective effects in models of Parkinson's disease, AD,hypoxia, ischemia, amyotrophic lateral sclerosis and glioma (L CCostantini, L J Barr, J L Vogel, S T Henderson BMC Neurosci. 2008, 9Suppl 2:S16) and improved cognitive scores in Alzheimers Diseasespatients (M A Reger, S T Henderson, C Hale, B Cholerton, L D Baker, G SWatson, K Hydea, D Chapmana, S Craft Neurobiology of Aging 25 (2004)311-314). The end result of increased ketone levels is an improvement inmitochondrial efficiency and reduction in the generation of reactiveoxygen species (for reviews see L C Costantini, L J Barr, J L Vogel, S THenderson BMC Neurosci. 2008, 9 Suppl 2:S16; K W Barañano, A L Hartman.Curr Treat Options Neurol. 2008; 10:410-9).

Furthermore, the potential of ACC inhibitors as antifungal agents and asantibacterial agents is well documented (L. Tong, H J Harwood Jr.Journal of Cellular Biochemistry 99:1476-1488, 2006). In addition, ACCinhibitors can be used to combat viral infections. It was discoveredrecently that viruses rely on the metabolic network of their cellularhosts to provide energy and building blocks for viral replication(Munger J, B D Bennett, A Parikh, X J Feng, J McArdle, H A Rabitz, TShenk, J D Rabinowitz. Nat. Biotechnol. 2008; 26:1179-86). A fluxmeasurement approach to quantify changes in metabolic activity inducedby human cytomegalovirus (HCMV) elucidated that infection with HCMVmarkedly changed fluxes through much of the central carbon metabolism,including glycolysis, tricarboxylic acid cycle and fatty acidbiosynthesis. Pharmacological inhibition of fatty acid biosynthesissuppressed the replication of two divergent enveloped viruses (HCMV andinfluenza A) indicating that fatty acid synthesis is essential for thereplication. These examples show that acetyl-CoA fluxes and de novofatty acid biosynthesis are critical to viral survival and propagationas the newly synthesized fatty acids and phospholipids are important forformation of viral envelopes. Changing the metabolic flux influences theabsolute quantity of phospholipid available, the chemical compositionand physical properties of the envelope negatively affect viral growthand replication. Hence, ACC inhibitors acting on key enzymes in thefatty acid metabolism, have the potential to be antiviral drugs.

AIM OF THE PRESENT INVENTION

The aim of the present invention is to provide new compounds, inparticular new piperidine derivatives, which are active with regard toacetyl-CoA carboxylase(s).

Another aim of the present invention is to provide new compounds, inparticular new piperidine derivatives, which are active with regard toACC2.

A further aim of the present invention is to provide new compounds, inparticular new piperidine derivatives, which have an inhibitory effecton acetyl-CoA carboxylase(s) in vitro and/or in vivo and possesssuitable pharmacological and pharmacokinetic properties to use them asmedicaments.

A further aim of the present invention is to provide new compounds, inparticular new piperidine derivatives, which have an inhibitory effecton ACC2 in vitro and/or in vivo and possess suitable pharmacological andpharmacokinetic properties to use them as medicaments.

A further aim of the present invention is to provide effective ACCinhibitors, in particular for the treatment of metabolic disorders, forexample of obesity and/or diabetes.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of acetyl-CoAcarboxylase(s) in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of the new compounds, in particular piperidine derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of the newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

OBJECT OF THE INVENTION

Within the scope of the present invention it has now surprisingly beenfound that the new compounds of general formula (I) as describedhereinafter exhibit an inhibiting activity with regard to acetyl-CoAcarboxylase(s).

According to another aspect of the present invention it has been foundthat the new compounds of general formula (I) as described hereinafterexhibit an inhibiting activity with regard to ACC2.

In a first aspect the present invention provides a compound of generalformula (I)

wherein

-   Ar¹ is selected from the group Ar¹-G1 consisting of:    -   6- to 10 membered arylene and 5- to 10-membered heteroarylene        all of which may be optionally substituted with one or more        substituents R^(A), wherein R¹ and R^(A) linked to adjacent        C-atoms of Ar¹ may be connected with each other and together        form a C₃₋₅-alkylene bridging group in which 1, 2 or        3-CH₂-groups may be replaced by O, C(═O), S, S(═O), S(═O)₂, NH        or N(C₁₋₄-alkyl)-, wherein the alkylene bridge may optionally be        substituted by one or two C₁₋₃-alkyl groups;-   R^(A) is selected from the group R^(A)-G1 consisting of:    -   H, F, Cl, Br, I, CN, OH, —NO₂, C₁₋₄-alkyl, C₂₋₄-alkenyl,        C₁₋₄-alkyl-O—, C₃₋₇-cycloalkyl-O—, C₁₋₄-alkyl-C(═O)—, H₂N—,        H₂N—C(═O)—, H₂N—S(═O)₂—, HO—C(═O)—, C₁₋₄-alkyl-O—C(═O)—, phenyl        and phenyl-C₁₋₃-alkyl,        -   wherein in each NH₂-group, one or both hydrogen atoms may            independently be replaced by C₁₋₄-alkyl;        -   wherein each alkyl or cycloalkyl may be optionally            substituted with one or more substituents selected from F            and OH;-   Ar² is selected from the group Ar²-G1 consisting of:    -   phenylene and a 5- or 6-membered monocyclic aromatic ring        containing 1, 2 or 3 heteroatoms selected from N, O, or S,        -   wherein all of the before mentioned groups may be optionally            substituted with one or more substituents R^(A);-   L is selected from the group L-G1 consisting of:    -   straight-chain C₁₋₄-alkylene, which may optionally be        substituted with one or two C₁₋₃-alkyl groups;-   R¹ is selected from the group R¹-G1 consisting of:    -   OH, C₁₋₄-alkyl-O—, C₃₋₇-cycloalkyl-O—, H₂N—, (C₁₋₄-alkyl)NH—,        (C₁₋₄-alkyl)₂N—, C₃₋₇-cycloalkyl-NH—,        C₃₋₇-cycloalkyl-C₁₋₃-alkyl-NH—, C₁₋₄-alkyl-C(═O)—,        C₁₋₄-alkyl-S(═O)₂—, HO—C(═O)—, C₁₋₄-alkyl-O—C(═O)—, H₂N—C(═O)—,        (C₁₋₄-alkyl)HN—C(═O)—, heterocyclyl-O—,        heterocyclyl-C₁₋₃-alkyl-O—, aryl-O—, aryl-C₁₋₃-alkyl-O—, and        (C₁₋₄-alkyl)₂N—C(═O)—,        -   wherein each alkyl or cycloalkyl may be optionally            substituted with one or more substituents selected from F            and OH;-   R² is selected from the group R²-G1 consisting of: H and C₁₋₃-alkyl;    and-   R³ is selected from the group R³-G1 consisting of:    -   H, C₁₋₆-alkyl, —O—(C₁₋₄-alkyl), C₃₋₁₀-carbocyclyl,        C₃₋₁₀-carbocyclyl-C₁₋₃-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl,        R^(N1)R^(N2)N—, heterocyclyl, heterocyclyl-C₁₋₃-alkyl, aryl,        aryl-C₁₋₃-alkyl, heteroaryl and heteroaryl-C₁₋₃-alkyl,        -   wherein each aryl, heteroaryl, carbocyclyl and heterocyclyl            may be optionally substituted with one or more C₁₋₄-alkyl,            and        -   wherein in each carbocyclyl and heterocyclyl a —CH₂-group            may optionally be replaced by —C(═O)—, and        -   wherein each alkyl, carbocyclyl, heterocyclyl, aryl and            heteroaryl group may be optionally substituted with one or            more substituents R⁴; wherein-   R⁴ is selected from the group R⁴-G1 consisting of:    -   F, Cl, Br, CN, OH, O₁₋₄-alkyl, —O—(C₁₋₄-alkyl), —S—(C₁₋₄-alkyl),        and —NH—C(═O)—C₁₋₃-alkyl;-   R^(N1) is selected from the group R^(N1)-G1 consisting of:    -   H and C₁₋₃-alkyl; and-   R^(N2) is selected from the group R^(N2)-G1 consisting of:    -   H, C₁₋₃-alkyl, O₃₋₁₀-carbocyclyl, C₃₋₁₀-carbocyclyl-C₁₋₃-alkyl,        C₃₋₆-alkenyl, C₃₋₆-alkynyl, heterocyclyl,        heterocyclyl-C₁₋₃-alkyl, aryl, aryl-C₁₋₃-alkyl, heteroaryl and        heteroaryl-C₁₋₃-alkyl,    -   wherein each carbocyclyl and heterocyclyl may be optionally        substituted with one or more C₁₋₄-alkyl, aryl or        aryl-C₁₋₃-alkyl-, and    -   wherein in each carbocyclyl and heterocyclyl a CH₂-group may        optionally be replaced by —C(═O)—; and    -   wherein each alkyl or cycloalkyl may be optionally substituted        with one or more substituents selected from F and OH; and    -   with the provision that there is at least one CH₂-group between        any double or triple bond of the alkenyl and alkynyl groups and        the nitrogen atom to which they are attached;        including any tautomers and stereoisomers thereof,        or a salt thereof        or a solvate or hydrate thereof.

In a further aspect the present invention relates to processes forpreparing a compound of general formula (I) and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula (I) according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula (I) orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by inhibiting the activity ofacetyl-CoA carboxylase(s) in a patient in need thereof characterized inthat a compound of general formula (I) or a pharmaceutically acceptablesalt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula (I) or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a cardiovascular disease or disorder in a patient in needthereof characterized in that a compound of general formula (I) or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a neurodegenerative disease or disorder or for treating adisease or disorder of the central nervous system in a patient in needthereof characterized in that a compound of general formula (I) or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a cancer, a malignant disorder or a neoplasia in a patientin need thereof characterized in that a compound of general formula (I)or a pharmaceutically acceptable salt thereof is administered to thepatient.

According to another aspect of the invention, there is provided the useof a compound of the general formula (I) or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for atherapeutic method as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula (I) or a pharmaceutically acceptablesalt thereof for a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the inhibition of acetyl-CoAcarboxylase(s) in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula (I) or a pharmaceuticallyacceptable salt thereof in combination with a therapeutically effectiveamount of one or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula (I) or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment or prevention of diseases or conditions which are mediated bythe inhibition of acetyl-CoA carboxylase(s).

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula (I)or a pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly Ar¹, Ar², R¹, R², R³ and L, are defined as above andhereinafter. If residues, substituents, or groups occur several times ina compound, as for example R^(A), R^(N1), R^(N2) or R⁴, they may havethe same or different meanings. Some preferred meanings of individualgroups and substituents of the compounds according to the invention willbe given hereinafter. Any and each of these definitions may be combinedwith each other.

Ar¹:

Ar¹-G1:

The group Ar¹ is preferably selected from the group Ar¹-G1 as definedhereinbefore and hereinafter.

Ar¹-G2:

In one embodiment the group Ar¹ is selected from the group Ar¹-G2consisting of: phenylene, naphthylene, pyridylene, 2H-pyridin-2-onylene,pyrimidinylene, pyridazinylene, pyrazinylene, quinolinylene,indan-1-onylene, benzo[1,3]dioxolylene,2,3-dihydro-benzo[1,4]dioxinylene and3,4-dihydro-2H-benzo[b][1,4]dioxepinylene,

-   -   wherein the before mentioned bicyclic groups preferably are        linked to the ring of the core structure of the formula (I) via        an aromatic or heteroaromatic ring of the bicyclic group, and    -   wherein all of the before mentioned groups may be optionally        substituted with one or more substituents R^(A).        Ar¹-G3:

In another embodiment the group Ar¹ is selected from the group Ar¹-G3consisting of: phenylene and pyridinylene,

-   -   wherein each of the beforementioned groups may be substituted        with a substituent R^(A).        Ar¹-G3a:

In another embodiment the group Ar¹ is selected from the group Ar¹-G3aconsisting of: phenylene, which may be substituted with R^(A).

Ar¹-G4:

In another embodiment the group Ar¹ is selected from the group Ar¹-G4consisting of:

wherein the asterisk to the right side of each group indicates the bondwhich is connected to the piperidine ring of the core structure of theformula (I), and the asterisk to the left side of each group indicatesthe bond which is connected to a substituent R¹, and in addition each ofthe before mentioned groups is optionally substituted with a substituentR^(A).Ar¹-G4a:

In another embodiment the group Ar¹ is selected from the group Ar¹-G4aconsisting of:

wherein the asterisk to the right side of each group indicates the bondwhich is connected to the piperidine ring of the core structure of theformula (I), and the asterisk to the left side of each group indicatesthe bond which is connected to a substituent R¹, and in addition each ofthe before mentioned phenyl groups is optionally substituted with F,—CH₃ or —OCH₃.Ar¹-G4b:

In another embodiment the group Ar¹ is selected from the group Ar¹-G4bconsisting of:

wherein the beforementioned 1,4-phenylene group is optionallysubstituted with F, —CH₃ or —OCH₃.Ar¹-G5:

In another embodiment the group Ar¹ is selected from the group Ar¹-G5consisting of:

wherein the before mentioned group is optionally substituted with F,—CH₃ or —OCH₃Ar¹-G5a:

In another embodiment the group Ar¹ is selected from the group Ar¹-G5aconsisting of:

wherein the asterisk to the right side of the cyclic group indicates thebond which is connected to the piperidine ring of the core structure ofthe formula (I), and the asterisk to the left side of the cyclic groupindicates the bond which is connected to a substituent R¹.Ar¹-G6:

In another embodiment the group Ar¹ is selected from the group Ar¹-G6consisting of:

R^(A):R^(A)-G1:

The group R^(A) is preferably selected from the group R^(A)-G1 asdefined hereinbefore and hereinafter.

R^(A)-G2:

In another embodiment the group R^(A) is selected from the groupR^(A)-G2 consisting of: H, F, Cl, Br, CN, OH, —NO₂, C₁₋₄-alkyl,C₁₋₄-alkyl-O—, H₂N—, C₁₋₆-alkyl-O—C(═O)—, phenyl and phenyl-CH₂—,

-   -   wherein in each NH₂-group, one or both hydrogen atoms may        independently be replaced by O₁₋₄-alkyl.        R^(A)-G3:

In another embodiment the group R^(A) is selected from the groupR^(A)-G3 consisting of:

H, F, Cl, CN, OH, C₁₋₃-alkyl and C₁₋₃-alkyl-O—.

R^(A)-G4:

In another embodiment the group R^(A) is selected from the groupR^(A)-G4 consisting of: H, F, —CH₃ and —OCH₃.

R^(A)-G5:

In another embodiment the group R^(A) is selected from the groupR^(A)-G5 consisting of: H, —CH₃ and —OCH₃.

Ar²:

Ar²-G1:

The group Ar² is preferably selected from the group Ar²-G1 as definedhereinbefore and hereinafter.

Ar²-G2:

In another embodiment the group Ar² is selected from the group Ar²-G2consisting of: phenylene, which may be optionally substituted with oneor two substituents R^(A).

Ar²-G2a:

In another embodiment the group Ar² is selected from the group Ar²-G2aconsisting of: phenylene, which may be optionally substituted with F or—OCH₃.

Ar²-G2b:

In another embodiment the group Ar² is selected from the group Ar²-G2bconsisting of: phenylene, which may be optionally substituted with oneF.

Ar²-G3:

In another embodiment the group Ar² is selected from the group Ar²-G3consisting of:

wherein the asterisk to the left side of each group indicates the bondwhich is connected to the piperidine ring of the core structure of theformula (I), and the asterisk to the right side of each group indicatesthe bond which is connected to L.Ar²-G3a:

In another embodiment the group Ar² is selected from the group Ar²-G3aconsisting of:

L:L-G1:

The group L is preferably selected from the group L-G1 as definedhereinbefore and hereinafter.

L-G2:

In another embodiment the group L is selected from the group L-G2consisting of: straight-chain C₁₋₄-alkylene, which may optionally besubstituted with one or two methyl groups.

L-G3:

In another embodiment the group L is selected from the group L-G3consisting of: straight-chain C₁₋₃-alkylene, which may optionally besubstituted with one or two methyl groups.

L-G3a:

In another embodiment the group L is selected from the group L-G3aconsisting of: straight-chain C₁₋₃-alkylene, which may optionally besubstituted with one methyl group.

L-G4:

In another embodiment the group L is selected from the group L-G4consisting of:

L-G4a:

In another embodiment the group L is selected from the group L-G4aconsisting of:

wherein the right-hand side of each of the before-mentioned moieties isattached to the N atom in formula (I) and the left-hand side of each ofthe before-mentioned moieties is attached to the Ar² group.L-G5:

In another embodiment the group L is selected from the group L-G5consisting of —CH(CH₃)—.

L-G5a:

According to another embodiment, the group L is selected from the groupL-G5a consisting of:

wherein the right-hand side of each of the before-mentioned moieties isattached to the N atom in formula (I) and the left-hand side of each ofthe before-mentioned moieties is attached to the Ar² group.

A preferred example of the group L-G5a is

wherein the right-hand side of the before-mentioned moiety is attachedto the N atom in formula (I) and the left-hand side of thebefore-mentioned moiety is attached to the Ar² group.

Another preferred example of the group L-G5a is

wherein the right-hand side of the before-mentioned moiety is attachedto the N atom in formula (I) and the left-hand side of thebefore-mentioned moiety is attached to the Ar² group.R¹R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore and hereinafter.

R¹-G2:

In another embodiment the group R¹ is selected from the group R¹-G2consisting of: OH, C₁₋₄-alkyl-O—, C₃₋₇-cycloalkyl-O—, H₂N—,(C₁₋₄-alkyl)NH—, (C₁₋₄-alkyl)₂N—, C₃₋₇-cycloalkyl-NH— andC₃₋₇-cycloalkyl-N(C₁₋₄-alkyl)-,

-   -   wherein each alkyl or cycloalkyl may be optionally substituted        with one or more substituents selected from F and OH.        R¹-G3:

In another embodiment the group R¹ is selected from the group R¹-G3consisting of: C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,C₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—, H₂N—, (C₁₋₄-alkyl)NH—, (C₁₋₃-alkyl)₂N—,C₃₋₆-cycloalkyl-NH— and C₃₋₇-cycloalkyl-N(C₁₋₄-alkyl)-,

-   -   wherein each alkyl or cycloalkyl may be optionally substituted        with one or more F atoms.        R¹-G4:

In another embodiment the group R¹ is selected from the group R¹-G4consisting of: C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O— andC₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—,

-   -   wherein each alkyl and cycloalkyl may be optionally substituted        with one or more F atoms.        R¹-G4a:

In another embodiment the group R¹ is selected from the group R¹-G4aconsisting of: C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O— andC₃₋₆-cycloalkyl-CH₂—O—,

-   -   wherein each alkyl and cycloalkyl may be optionally substituted        with one or two F atoms.        R¹-G4b:

In another embodiment the group R¹ is selected from the group R¹-G4bconsisting of: C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O— andC₃₋₆-cycloalkyl-CH₂—O—,

-   -   wherein each cycloalkyl may be optionally substituted with one        or two F atoms.        R¹-G5:

In another embodiment the group R¹ is selected from the group R¹-G5consisting of: C₁₋₄-alkyl-O—, C₃₋₄-cycloalkyl-O— andC₃₋₄-cycloalkyl-CH₂—O—,

-   -   wherein each alkyl and cycloalkyl may be optionally substituted        with one or two F atoms.        R¹-G5a:

In another embodiment the group R¹ is selected from the group R¹-G5aconsisting of: C₁₋₄-alkyl-O—, C₃₋₄-cycloalkyl-O— andC₃₋₄-cycloalkyl-CH₂—O—,

-   -   wherein each cycloalkyl may be optionally substituted with one        or two F atoms.        R¹-G5b:

In another embodiment the group R¹ is selected from the group R¹-G5bconsisting of: C₁₋₃-alkyl-O—, cyclobutyl-O— and cyclopropyl-CH₂—O—,

-   -   wherein the cyclopropyl group may be optionally substituted with        one or preferably two F atoms.        R²        R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore and hereinafter.

R²-G2:

In another embodiment the group R² is selected from the group R²-G2consisting of: H and CH₃.

R²-G3:

In another embodiment the group R² is selected from the group R²-G3consisting of: H.

R³

R³-G1:

The group R³ is preferably selected from the group R³-G1 as definedhereinbefore and hereinafter.

R³-G2:

In another embodiment the group R³ is selected from the group R³-G2consisting of: C₁₋₄-alkyl, —O—(C₁₋₃-alkyl), C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, R^(N1)R^(N2)N—,heterocyclyl, heterocyclyl-CH₂—, aryl, aryl-CH₂—, heteroaryl andheteroaryl-CH₂—,

-   -   wherein in each heterocyclyl a —CH₂-group may optionally be        replaced by —C(═O)—, and    -   wherein each alkyl, carbocyclyl, heterocyclyl, aryl and        heteroaryl group may be optionally substituted with one or more        substituents R⁴; wherein    -   R⁴ is selected from the group R⁴-G1 consisting of:    -   F, Cl, Br, CN, OH, C₁₋₄-alkyl, —O—(C₁₋₄-alkyl), —S—(C₁₋₄-alkyl),        and —NH—C(═O)—C₁₋₃-alkyl;        R³-G3:

In another embodiment the group R³ is selected from the group R³-G3consisting of: C₁₋₃-alkyl, —O—(C₁₋₂-alkyl), C₃₋₅-cycloalkyl,C₃₋₅-cycloalkyl-CH₂—, R^(N1)N^(R2)N—, morpholinyl, heteroaryl andheteroaryl-CH₂—,

-   -   wherein each alkyl may be optionally substituted with one to        three F atoms and/or one CN, OH, —O—(C₁₋₃-alkyl) and —S—CH₃, and    -   wherein each cycloalkyl may be optionally substituted with one        CN, OH, or C₁₋₃-alkyl, and    -   wherein each heteroaryl group may be optionally substituted with        one or more substituents independently selected from the group        consisting of C₁₋₃-alkyl and —NH—C(═O)—C₁₋₃-alkyl.        R³-G4:

In another embodiment the group R³ is selected from the group R³-G4consisting of: C₁₋₃-alkyl, —O—(C₁₋₂-alkyl), C₃₋₅-cycloalkyl,R^(N1)R^(N2)N—, morpholinyl, heteroaryl and heteroaryl-CH₂—,

-   -   wherein each alkyl may be optionally substituted with one to        three F atoms or one CN, OH, —O—CH₃ and —S—CH₃, and    -   wherein each cycloalkyl may be optionally substituted with one        CN, OH, or —CH₃, and    -   wherein each heteroaryl group is selected from the group        consisting of pyrrolyl, imidazolyl, pyrazolyl, oxazoly,        thiazolyl, benzimidazolyl and pyridinyl, and    -   wherein each heteroaryl group may be optionally substituted with        one or more substituents independently selected from the group        consisting of phenyl, —CH₃ and —NH—C(═O)—CH₃, and    -   wherein R^(N1) is selected from the group consisting of H and        C₁₋₃-alkyl, and    -   wherein R^(N2) is selected from the group consisting of H,        C₁₋₃-alkyl and pyridinyl.        R³-G5:

In another embodiment the group R³ is selected from the group R³-G5consisting of: C₁₋₃-alkyl, —O—CH₃, cyclopropyl, R^(N1)R^(N2)N—,morpholinyl, heteroaryl and heteroaryl-CH₂—,

-   -   wherein each alkyl may be optionally substituted with one to        three F atoms or one CN, OH, —O—CH₃ and —S—CH₃, and    -   wherein each cycloalkyl may be optionally substituted with one        CN, or —CH₃, and    -   wherein each heteroaryl group is selected from the group        consisting of pyrrolyl, pyrazolyl, oxazolyl, thiazolyl and        pyridinyl, and wherein each heteroaryl group may be optionally        substituted with one or two substituents independently selected        from the group consisting of —CH₃ and —NH—C(═O)—CH₃, and    -   wherein R^(N1) is selected from the group consisting of H and        C₁₋₂-alkyl, and,    -   wherein R^(N2) is selected from the group consisting of H,        C₁₋₃-alkyl and pyridinyl.        R³-G5a:

In another embodiment the group R³ is selected from the group R³-G5aconsisting of: C₁₋₃-alkyl, —CH₂F, —CHF₂, —CF₃, —CHF—CH₃, —CH₂—OH,—CH₂—OCH₃, —CH₂—S—CH₃, —OCH₃, —N(C₁₋₂-alkyl)₂,

R³-G6:

In another embodiment the group R³ is selected from the group R³-G6consisting of: —CH₃, cyclopropyl and —N(CH₃)₂.

R³-G6a:

In another embodiment the group R³ is selected from the group R³-G6aconsisting of: —CH₃ and cyclopropyl.

R³-G6b:

In another embodiment the group R³ is selected from the group R³-G6bconsisting of: —CH₃.

R⁴

R⁴-G1:

The group R⁴ is preferably selected from the group R⁴-G1 as definedhereinbefore and hereinafter.

R⁴-G2:

In another embodiment the group R⁴ is selected from the group R⁴-G2consisting of: F, Cl, Br, C₁₋₃-alkyl, —O—(C₁₋₃-alkyl) and—NH—C(═O)—C₁₋₃-alkyl;

R⁴-G3:

In another embodiment the group R⁴ is selected from the group R⁴-G3consisting of: —C₁₋₃-alkyl and —NH—C(═O)—C₁₋₃-alkyl.

R⁴-G4:

In another embodiment the group R⁴ is selected from the group R⁴-G4consisting of: —CH₃ and —NH—C(═O)—CH₃.

R^(N1)

R^(N1)-G1:

The group R^(N1) is preferably selected from the group R^(N1)-G1 asdefined hereinbefore and hereinafter.

In another embodiment the group R^(N1) is selected from the groupR^(N1)-G2 consisting of: H, methyl and ethyl.

In another embodiment the group R^(N1) is selected from the groupR^(N1)-G3 consisting of: methyl.

R^(N2)

The group R^(N2) is preferably selected from the group R^(N2)-G1 asdefined hereinbefore and hereinafter.

R^(N2)-G2:

In another embodiment the group R^(N2) is selected from the groupR^(N2)-G2 consisting of: H, C₁₋₃-alkyl, C₃₋₇-cycloalkyl-, phenyl,pyridinyl and pyrimidinyl.

R^(N2)-G3:

In another embodiment the group R^(N2) is selected from the groupR^(N2)-G3 consisting of: H, C₁₋₃-alkyl and pyridinyl.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula (I)are defined according to the definitions set forth hereinbefore:

Embodiment R¹ Ar¹ R^(A) Ar² L R² R³ E-1 R¹-G1 Ar¹-G1 R^(A)-G1 Ar²-G1L-G1 R²-G1 R³-G1 E-2 R¹-G2 Ar¹-G2 R^(A)-G2 Ar²-G1 L-G2 R²-G2 R³-G2 E-3R¹-G3 Ar¹-G2 R^(A)-G3 Ar²-G2 L-G3 R²-G2 R³-G3 E-4 R¹-G3 Ar¹-G3 R^(A)-G4Ar²-G2 L-G3 R²-G2 R³-G3 E-5 R¹-G4 Ar¹-G3 R^(A)-G4 Ar²-G2 L-G3 R²-G2R³-G3 E-6 R¹-G4a Ar¹-G3 R^(A)-G4 Ar²-G2 L-G3 R²-G2 R³-G4 E-7 R¹-G5Ar¹-G3 R^(A)-G4 Ar²-G2 L-G3 R²-G2 R³-G4 E-8 R¹-G3 Ar¹-G3 R^(A)-G4Ar²-G2a L-G3 R²-G2 R³-G3 E-9 R¹-G4 Ar¹-G3 R^(A)-G4 Ar²-G2a L-G3 R²-G2R³-G3 E-10 R¹-G4a Ar¹-G3 R^(A)-G4 Ar²-G2a L-G3 R²-G2 R³-G4 E-11 R¹-G5Ar¹-G3 R^(A)-G4 Ar²-G2a L-G3 R²-G2 R³-G4 E-12 R¹-G4a Ar¹-G3 R^(A)-G4Ar²-G3a L-G4a R²-G3 R³-G4 E-13 R¹-G5 Ar¹-G3 R^(A)-G5 Ar²-G3a L-G4a R²-G3R³-G4 E-14 R¹-G4a Ar¹-G3 R^(A)-G4 Ar²-G3a L-G4a R²-G3 R³-G5 E-15 R¹-G5Ar¹-G3 R^(A)-G5 Ar²-G3a L-G4a R²-G3 R³-G5 E-16 R¹-G4a Ar¹-G3 R^(A)-G5Ar²-G3a L-G5 R²-G3 R³-G4 E-17 R¹-G5 Ar¹-G3 R^(A)-G5 Ar²-G3a L-G5 R²-G3R³-G5 E-18 R¹-G5a Ar¹-G3 R^(A)-G5 Ar²-G3a L-G5 R²-G3 R³-G5

The following preferred embodiments of compounds of the formula (I) aredescribed using generic formulae (I.1) to (I.5), wherein any tautomersand stereoisomers, solvates, hydrates and salts thereof, in particularthe pharmaceutically acceptable salts thereof, are encompassed.

wherein in each of the above formulae (I.1) to (I.5), the groups Ar¹,R^(A), R¹, R³ and L are defined as hereinbefore and hereinafter.

Preferred embodiments of the above formulae (I.1) to (I.5) according tothe present invention are set forth in the following table, wherein eachgroup Ar¹, R^(A), R¹, R³ and L of each embodiment is defined accordingto the definitions set forth hereinbefore and wherein all othersubstituents of the formula (I) are defined according to the definitionsset forth hereinbefore. Preferred embodiments include:

Embodiment Formula Ar¹ R^(A) R¹ R³ L E-A (I.1) Ar¹-G3 R^(A)-G4 R¹-G4R³-G3 L-G3a E-B (I.1) Ar¹-G3 R^(A)-G4 R¹-G4 R³-G5 L-G3a E-C (I.1) Ar¹-G3R^(A)-G4 R¹-G4 R³-G4 L-G4 E-D (I.1) Ar¹-G3 R^(A)-G4 R¹-G5 R³-G3 L-G3aE-E (I.1) Ar¹-G3 R^(A)-G4 R¹-G5 R³-G4 L-G4 E-F (I.1) Ar¹-G4 R^(A)-G4R¹-G4 R³-G3 L-G3a E-G (I.1) Ar¹-G4 R^(A)-G4 R¹-G4 R³-G3 L-G4 E-H (I.1)Ar¹-G4 R^(A)-G4 R¹-G4 R³-G4 L-G4 E-I (I.1) Ar¹-G4a — R¹-G4 R³-G4 L-G4E-J (I.1) Ar¹-G4a — R¹-G5 R³-G5 L-G4 E-K (I.1) Ar¹-G5a — R¹-G5 R³-G5L-G4 E-L (I.1a) Ar¹-G3 R^(A)-G4 R¹-G4 R³-G3 L-G3a E-M (I.1a) Ar¹-G5a —R¹-G4 R³-G4 L-G4 E-N (I.1b) Ar¹-G4b R^(A)-G4 R¹-G4 R³-G3 — E-O (I.1b)Ar¹-G4b R^(A)-G4 R¹-G5 R³-G4 — E-P (I.1b) Ar¹-G4b R^(A)-G4 R¹-G5 R³-G5 —E-Q (I.2) — R^(A)-G4 R¹-G4b R³-G5 L-G4 E-R (I.2) — R^(A)-G4 R¹-G4b R³-G6L-G4 E-S (I.2a) — — R¹-G4 R³-G4 L-G4a E-T (I.2a) — — R¹-G4 R³-G6 L-G4aE-U (I.2b) — R^(A)-G4 R¹-G4 R³-G4 — E-V (I.2b) — R^(A)-G4 R¹-G4 R³-G6 —E-W (I.2c) — — R¹-G4 R³-G4 — E-X (I.2c) — — R¹-G4 R³-G6 — E-Y (I.3) —R^(A)-G5 R¹-G5 R³-G6b L-G5a E-Z (I.3a) — R^(A)-G5 R¹-G5 R³-G6b — E-AA(I.4) — R^(A)-G5 R¹-G5a R³-G6a — E-BB (I.5) — R^(A)-G5 R¹-G5a R³-G6a —including any tautomers and stereoisomers, solvates, hydrates and saltsthereof, in particular the pharmaceutically acceptable salts thereof.

A preferred embodiment of the present invention concerns those compoundsof general formula (I), wherein

Ar¹ is selected from the group Ar¹-G4b consisting of:

-   -   wherein the beforementioned 1,4-phenylene group is optionally        substituted with F, —CH₃ or —OCH₃;        Ar² is selected from the group Ar²-G3 consisting of:

-   -   wherein the asterisk to the left side of each group indicates        the bond which is connected to the piperidine ring of the core        structure of the formula (I), and the asterisk to the right side        of each group indicates the bond which is connected to L;        L is selected from the group L-G5a consisting of:

R¹ is selected from the group R¹-G5a consisting of:C₁₋₄-alkyl-O—, C₃₋₄-cycloalkyl-O— and C₃₋₄-cycloalkyl-CH₂—O—,

-   -   wherein each alkyl or cycloalkyl may be optionally substituted        with one to three F atoms;        R² is selected from the group R²-G3 consisting of: H; and        R³ is selected from the group R³-G5 consisting of:        C₁₋₃-alkyl, —O—CH₃, cyclopropyl, R^(N1)R^(N2)N—, morpholinyl,        heteroaryl and heteroaryl-CH₂—,    -   wherein each alkyl may be optionally substituted with one to        three F atoms or one CN, OH, —O—CH₃ and —S—CH₃, and    -   wherein each cycloalkyl may be optionally substituted with one        CN, or —CH₃, and    -   wherein each heteroaryl group is selected from the group        consisting of pyrrolyl, pyrazolyl, oxazoly, thiazolyl and        pyridinyl, and    -   wherein each heteroaryl group may be optionally substituted with        one or two substituents independently selected from the group        consisting of —CH₃ and —NH—C(═O)—CH₃, and    -   wherein R^(N1) is selected from the group consisting of H and        C₁₋₂-alkyl, and,    -   wherein R^(N2) is selected from the group consisting of H,        C₁₋₃-alkyl and pyridinyl;        and the tautomers, enantiomers and pharmaceutically acceptable        salts thereof.

A more preferred embodiment of the present invention concerns thosecompounds of general formula (I), wherein

Ar¹ is selected from the group Ar¹-G4b consisting of:

-   -   wherein the beforementioned 1,4-phenylene group is optionally        substituted with F, —CH₃ or —OCH₃;        Ar² is selected from the group Ar²-G3 consisting of:

-   -   wherein the asterisk to the left side of each group indicates        the bond which is connected to the piperidine ring of the core        structure of the formula (I), and the asterisk to the right side        of each group indicates the bond which is connected to L;        L is selected from the group L-G5a consisting of:

R¹ is selected from the group R¹-G5a consisting of:C₁₋₄-alkyl-O—, C₃₋₄-cycloalkyl-O— and C₃₋₄-cycloalkyl-CH₂—O—,

-   -   wherein each cycloalkyl may be optionally substituted with one        or two F atoms;        R² is selected from the group R²-G3 consisting of: H; and        R³ is selected from the group R³-G6 consisting of:        —CH₃, cyclopropyl and —N(CH₃)₂;        and the tautomers, enantiomers and pharmaceutically acceptable        salts thereof.

An even more preferred embodiment of the present invention concernsthose compounds of general formula (I), wherein

Ar¹ is selected from the group Ar¹-G6 consisting of:

Ar² is selected from the group Ar²-G3a consisting of:

L is selected from the group L-G5a consisting of:

R¹ is selected from the group R¹-G5a consisting of:C₁₋₄-alkyl-O—, C₃₋₄-cycloalkyl-O— and C₃₋₄-cycloalkyl-CH₂—O—,

-   -   wherein each cycloalkyl may be optionally substituted with one        or two F atoms;        R² is selected from the group R²-G3 consisting of: H; and        R³ is selected from the group R³-G6 consisting of:        —CH₃, cyclopropyl and —N(CH₃)₂;        and the tautomers, enantiomers and pharmaceutically acceptable        salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

Synthesis Schemes

The compounds according to the invention may be obtained using methodsof synthesis which are known to the one skilled in the art and describedin the literature of organic synthesis. Preferably the compounds areobtained analogously to the methods of preparation explained more fullyhereinafter, in particular as described in the experimental section.

Compounds of general formula (I) may be prepared by palladium-mediatedBuchwald reactions or copper-mediated Ullmann reactions of arylhalogenides or aryl triflates (III) with piperidines (II) wherein Z is aleaving group which for example denotes Cl, Br, I or OTf (triflate).

Compounds of general formula (IV) may be prepared by reaction of amides(V) with alkylating reagents R²Z (VI) after deprotonation with basessuch as sodium hydride wherein Z is a leaving group which for exampledenotes Cl, Br, I, mesylate or triflate.

Compounds of general formula (IV) may be prepared by amide couplingreactions of amines (VII) with carboxylic acids (VIII) mediated bycoupling reagents such as eg TBTU, HOBt, HATU, CDT or CDI.

Compounds of general formula (IX) may be prepared by urea formingreactions such as reaction of amines (X) with carbamoyl chlorides (XI)or isocyanates (VII).

Alternatively, compounds of general formula (IX) may be prepared byreaction of amines (X) with amines (XIII) after reaction with reagentssuch as CDI or CDT.

Compounds of general formula (XIV), wherein R is C₁₋₄-alkyl, may beprepared by urethane forming reactions such as reaction of amines (X)with chloro formates (XV).

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refers to the inhibition of acetyl-CoAcarboxylase(s) (ACC) with one or more compounds of the presentinvention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk is may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

In the following the term bicyclic includes spirocyclic.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present inventionalso comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C (CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cylcoalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cylcoalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl, morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic-ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

All rests and substituents as defined hereinbefore and hereinafter maybe substituted with one or more F atoms. Preferred fluorinated alkylgroups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferredfluorinated alkoxy resp. alkyl-O— groups are fluoromethoxy,difluoromethoxy and trifluoromethoxy.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following ACC2 assay:

Spectrophotometric 384 Well Assay

Malonyl CoA formation by acetyl CoA carboxylases is stoichometricallylinked to the consumption of ATP. ACC2 activity is measured in aNADH-linked kinetic method measuring ADP generated during the ACCreaction using a coupled lactate dehydrogenase/pyruvate kinase reaction.

For biological testing, a human ACC2 construct which lacks the 128 aminoacids at the N-terminus for increased solubility (nt 385-6966 in Genbankentry AJ575592) is cloned. The protein is then expressed in insect cellsusing a baculoviral expression system. Protein purification is performedby anion exchange.

All compounds are dissolved in dimethyl sulfoxide (DMSO) to aconcentration of 10 mM.

Assay reactions are then carried out in 384-well plates, with hACC2 inan appropriate dilution and at final assay concentrations (f.c.) of 100mM Tris (pH 7.5), 10 mM trisodium citrate, 25 mM KHCO₃, 10 mM MgCl₂, 0.5mg/ml BSA, 3.75 mM reduced L-glutathione, 15 U/ml lactate dehydrogenase,0.5 mM phosphoenolpyruvate, 15 U/ml pyruvate kinase, compounds atdifferent concentrations at final DMSO concentrations of 1%.

The enzymatic reaction is then started by addition of a mixture of NADH,acetyl Coenzyme A (both 200 μM f.c.) and ATP (500 uM f.c.). The decreaseof the optical density (slope S) is then determined at 25° C. at awavelength of 340 nm over 15 minutes in a spectrophotometric reader.

Each assay microtiter plate contains wells with vehicle instead ofcompound as controls for the non-inhibited enzyme (100% CTL; ‘HIGH’) andwells without acetyl-CoA as controls for non-specific NADH degradation(0% CTL; ‘LOW’).

The slope S is used for calculation of %CTL=(S(compound)−S(‘LOW’))/(S(‘HIGH’)−S(‘LOW’))*100. Compounds will givevalues between 100% CTL (no inhibition) and 0% CTL (completeinhibition).

For IC₅₀ value determination, the sample slope in the presence of thetest compound after subtraction of the low controls(S(compound)−S(‘LOW’)) are used.

An IC₅₀ value is derived from the compound slopes at different dosagesafter subtraction of the low controls (S(compound)−S(‘LOW’)) bynon-linear regression curve fitting (equationy=(A+((B−A)/(1+((C/x)^D))))).

The compounds of general formula (I) according to the invention forexample have IC₅₀ values below 10000 nM, particularly below 1000 nM,preferably below 300 nM.

In the following table the activity expressed as IC₅₀ (μM) of compoundsaccording to the invention is presented wherein the IC₅₀ values aredetermined in the ACC2 assay as described hereinbefore. The term “Ex.”refers to the example numbers according to the following experimentalsection.

Example IC₅₀ [μM] 1.1 0.07 1.2 0.15 1.3 0.05 1.4 0.23 1.5 0.88 1.6 1.121.7 0.09 1.8 0.68 1.9 0.61 1.10 0.80 1.11 0.44 1.12 3.17 1.13 0.13 1.140.45 1.15 1.85 1.16 1.24 1.17 0.82 1.18 0.17 1.19 0.82 1.20 0.66 1.210.64 1.22 0.25 1.23 0.26 1.24 0.54 1.25 0.37 1.26 0.34 1.27 2.16 1.300.06 1.31 0.15 1.32 0.23 1.33 0.46 1.40 0.24 1.41 1.27 1.42 1.26 1.430.16 1.44 0.16 1.45 0.35 1.46 0.37 1.47 0.43 1.48 0.46 1.50 1.15 1.514.41 1.52 4.23 1.60 1.22 1.61 4.47 1.70 8.47 2.1 4.15 2.2 0.69 2.3 1.212.4 0.71 2.5 6.91 2.6 0.11 2.7 0.52 3.1 2.77 3.2 0.38 3.3 0.76 3.4 4.883.5 4.53 3.6 0.20 3.7 1.48 3.8 0.44 3.9 4.98 4.1 1.98 4.2 1.16 4.3 2.364.4 3.69 5.1 2.09 6.1 3.43

In view of their ability to inhibit acetyl-CoA carboxylase(s), thecompounds of general formula (I) according to the invention and thecorresponding salts thereof are theoretically suitable for thetreatment, including preventative treatment of all those diseases orconditions which may be affected or which are mediated by the inhibitionof acetyl-CoA carboxylase(s), in particular ACC2, activity.

Accordingly, the present invention relates to a compound of generalformula (I) as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula (I) for the treatment and/or prevention of diseases orconditions which are mediated by the inhibition of acetyl-CoAcarboxylase(s), in particular ACC2, in a patient, preferably in a human.

In yet another aspect the present invention relates a method fortreating, including preventing a disease or condition mediated by theinhibition of acetyl-CoA carboxylase(s) in a mammal that includes thestep of administering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutical composition thereof. Diseases andconditions mediated by inhibitors of acetyl-CoA carboxylases embracemetabolic and/or cardiovascular and/or neurodegenerative diseases orconditions.

According to one aspect the compounds of the present invention areparticularly suitable for treating diabetes mellitus, in particular Type2 diabetes, Type 1 diabetes, and diabetes-related diseases, such as ishyperglycemia, metabolic syndrome, impaired glucose tolerance, diabeticneuropathy, diabetic nephropathy, diabetic retinopathy, dyslipidemia,hypertension, hyperinsulinemia, and insulin resistance syndrome, hepaticinsulin resistance, including complications such as macro- andmicrovascular disorders, including thromboses, hypercoagulable andprothrombotic states (arterial and venous), high blood pressure,coronary artery disease and heart failure, increased abdominal girth,hypercoagulability, hyperuricemia, micro-albuminemia.

According to another aspect the compounds of the present invention areparticularly suitable for treating overweight, obesity, includingvisceral (abdominal) obesity, nonalcoholic fatty liver disease (NAFLD)and obesity related disorders, such as for example weight gain or weightmaintenance

Obesity and overweight are generally defined by body mass index (BMI),which is correlated with total body fat and estimates the relative riskof disease. BMI is calculated by weight in kilograms divided by heightin meters squared (kg/m²). Overweight is typically defined as a BMI of25-29.9 kg/m², and obesity is typically defined as a BMI of 30 kg/m² orgreater.

According to another aspect the compounds of the present invention areparticularly suitable for treating, including preventing, or delayingthe progression or onset of diabetes or diabetes-related disordersincluding Type 1 (insulin-dependent diabetes mellitus, also referred toas “IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, alsoreferred to as “NIDDM”) diabetes, impaired glucose tolerance, insulinresistance, hyperglycemia, pancreatic beta cell degeneration anddiabetic complications (such as macro- and microvascular disorders,atherosclerosis, coronary heart disease, stroke, peripheral vasculardisease, nephropathy, hypertension, neuropathy, and retinopathy).

In addition the compounds of the present invention are suitable fortreating dyslipidemias in general and more specifically elevated lipidconcentrations in the blood and in tissues, dysregulation of LDL, HDLand VLDL, in particular high plasma triglyceride concentrations, highpostprandial plasma triglyceride concentrations, low HDL cholesterolconcentration, low apoA lipoprotein concentrations, high LDL cholesterolconcentrations, high apoB lipoprotein concentrations, includingatherosclerosis, coronary heart disease, cerebrovascular disorders,diabetes mellitus, metabolic syndrome, obesity, insulin resistanceand/or cardiovascular disorders.

ACC inhibition may lead to a centrally stimulating effect on foodintake. Therefore compounds of the present invention may be suitable fortreating eating disorders such as anorexia nervosa.

In addition the compounds of the present invention may provideneuroprotective effects in patients with Parkinson's disease,Alzheimer's disease, hypoxia, ischemia, amyotrophic lateral sclerosis orglioma and may improve cognitive scores in Alzheimer's diseasespatients.

Further diseases and conditions mediated by inhibitors of acetyl-CoAcarboxylases embrace but are not limited to:

-   A. disorders of fatty acid metabolism and glucose utilization    disorders; disorders in which insulin resistance is involved;-   B. hepatic disorders and conditions related thereto, including:    fatty liver, hepatic steatosis, non-alcoholic hepatitis,    non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute    fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron    storage diseases, hepatic fibrosis, hepatic cirrhosis, hepatoma,    viral hepatitis;-   C. skin disorders and conditions and those associated with    polyunsaturated fatty acids, such as    -   eczema, acne, sebaceous gland diseases, psoriasis, keloid scar        formation or prevention, other diseases related to mucous        membrane fatty acid composition;-   D. primary hypertriglyceridemia or secondary hypertriglyceridemias    following familial histiocytic reticulosis, lipoprotein lipase    deficiency, hyperlipo-proteinemias, apolipoprotein deficiency (e.g.    apoClI or apoE deficiency);-   E. diseases or conditions related to neoplastic cellular    proliferation, for example benign or malignant tumors, cancer,    neoplasias, metastases, carcinogenesis;-   F. diseases or conditions related to neurological, psychiatric or    immune disorders or conditions;-   G. other diseases or conditions in which inflammatory reactions,    cell differentiation and/or other ACC-mediated aspects may for    example be involved are:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke, ischemic, stroke and transient        ischemic attack (TIA),    -   peripheral occlusive disease,    -   vascular restenosis or reocclusion,    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis,    -   pancreatitis,    -   sinusitis,    -   retinopathy, ischemic retinopathy,    -   adipose cell tumors,    -   lipomatous carcinomas such as, for example, liposarcomas,    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas,        breast cancer (in particular breast cancer with BRCA1        mutations), etc.,    -   tumors in which ACC is up regulated,    -   acute and chronic myeloproliferative disorders and lymphomas,        angiogenesis    -   neurodegenerative disorders including Alzheimer's disease,        multiple sclerosis, Parkinson's disease, epilepsy,    -   erythemato-squamous dermatoses such as, for example, psoriasis,    -   acne vulgaris,    -   other skin disorders and dermatological conditions which are        modulated by PPAR,    -   eczemas and neurodermatitis,    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis,    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratoses, photo-induced        keratoses or keratosis follicularis,    -   keloids and keloid prophylaxis,    -   bacterial infections,    -   fungal infections,    -   warts, including condylomata or condylomata acuminata    -   viral infections such as, for example, human hepatitis B virus        (HBV), hepatitis C virus (HCV), West Nile virus (WNV) or Dengue        virus, human Immunodeficiency virus (HIV), poxvirus and Vaccinia        virus (VV), HCMV, influenza A, human papilloma viral (HPV).        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia,    -   papular dermatoses such as, for example, lichen planus,    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas,    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi,    -   chilblains;    -   high blood pressure,    -   polycystic ovary syndrome (PCOS),    -   asthma,    -   cystic fibrosis,    -   osteoarthritis,    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example rheumatoid arthritis,    -   vasculitis,    -   wasting (cachexia),    -   gout,    -   ischemia/reperfusion syndrome,    -   acute respiratory distress syndrome (ARDS)    -   viral diseases and infections    -   lipodystrophy and lipodystrophic conditions, also for treating        adverse drug effect;    -   myophathies and lipid myopathis (such as carnitine        palmitoyltransferase I or II deficiency);-   H. formation of muscles and a lean body or muscle mass formation.

The dose range of the compounds of general formula (I) applicable perday is usually from 0.001 to 10 mg per kg body weight of the patient,preferably from 0.01 to 8 mg per kg body weight of the patient. Eachdosage unit may conveniently contain 0.1 to 1000 mg of the activesubstance, preferably it contains between 0.5 to 500 mg of the activesubstance.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula (I)will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. The content of the pharmaceutically active compound(s) isadvantageously in the range from 0.1 to 90 wt.-%, for example from 1 to70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula (I) with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsassociated with metabolic diseases or conditions such as for examplediabetes mellitus, obesity, diabetic complications, hypertension,hyperlipidemia.

Therefore a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofanti-obesity agents (including appetite suppressants), agents whichlower blood glucose, anti-diabetic agents, agents for treatingdyslipidemias, such as lipid lowering agents, anti-hypertensive agents,antiatherosclerotic agents, anti-inflammatory active ingredients, agentsfor the treatment of malignant tumors, antithrombotic agents, agents forthe treatment of heart failure and agents for the treatment ofcomplications caused by diabetes or associated with diabetes.

Suitable anti-obesity agents include 11beta-hydroxy steroiddehydrogenase-1 (11beta-HSD type 1) inhibitors, stearoyl-CoAdesaturase-1 (SCD-1) inhibitors, MCR-4 agonists, cholecystokinin-A(CCK-A) agonists, monoamine reuptake inhibitors, sympathomimetic agents,beta3 adrenergic agonists, dopamine agonists, melanocyte-stimulatinghormone analogs, 5HT2c agonists, melanin concentrating hormoneantagonists, leptin (the OB protein), leptin analogs, leptin agonists,galanin antagonists, lipase inhibitors, anorectic agents, neuropeptide-Yantagonists (e.g., NPY Y5 antagonists), PY_(Y3-36) (including analogsthereof), thyromimetic agents, dehydroepiandrosterone or an analogthereof, glucocorticoid agonists or antagonists, orexin antagonists,glucagon-like peptide-1 agonists, ciliary neurotrophic factors, humanagouti-related protein (AGRP) inhibitors, ghrelin antagonists, GOAT(Ghrelin O-Acyltransferase) inhibitors, histamine 3 antagonists orinverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g.,gut-selective MTP inhibitors), opioid antagonists, orexin antagonists,and the like.

Preferred anti-obesity agents for use in the combination aspects of thepresent invention include gut-selective MTP inhibitors CCKa agonists,5HT2c agonists, MCR4 agonists, lipase inhibitors, opioid antagonists,oleoyl-estrone, obinepitide, pramlintide (Symlin®), tesofensine(NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide(Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine.

Suitable anti-diabetic agents include sodium-glucose co-transporter(SGLT) inhibitors, 11beta-hydroxy steroid dehydrogenase-1 (11beta-HSDtype 1) inhibitors, phosphodiesterase (PDE) 10 inhibitors,diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas(e.g., acetohexamide, chiorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), meglitinides, analpha-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688),alpha-glucoside hydrolase inhibitors (e.g., acarbose), alpha-glucosidaseinhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol,voglibose, pradimicin-Q, and salbostatin), PPAR gamma agonists (e.g.,balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone,pioglitazone, rosiglitazone and troglitazone), PPAR alpha/gamma agonists(e.g., CLX-0940, GW-1536, GW-20 1929, GW-2433, KRP-297, L-796449, LR-90,MK-0767 and SB-219994), biguanides (e.g., metformin), GLP-1 derivatives,glucagon-like peptide 1 (GLP-1) agonists (e.g., Byetta™, exendin-3 andexendin-4), GLP-1 receptor and glucagon receptor co-agonists, glucagonreceptor antagonists, GIP receptor antagonists, protein tyrosinephosphatase-1 B (PTP-1 B) inhibitors (e.g., trodusquemine, hyrtiosalextract), SIRT-1 activators (e.g. reservatrol), dipeptidyl peptidease IV(DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin,linagliptin and saxagliptin), insulin secretagogues, GPR119 agonists,GPR40 agonists, TGR5 agonists, MNK2 inhibitors, GOAT (GhrelinO-Acyltransferase) inhibitors, fatty acid oxidation inhibitors, A2antagonists, c-jun amino-terminal kinase (JNK) inhibitors, insulins,insulin derivatives, fast acting insulins, inhalable insulins, oralinsulins, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2receptor agonists and glucokinase activators.

Preferred anti-diabetic agents are metformin, glucagon-like peptide 1(GLP-1) agonists (e.g., Byetta™), GLP-1 receptor and glucagon receptorco-agonists, sodium-glucose co-transporter (SGLT) inhibitors,11beta-hydroxy steroid dehydrogenase-1 (11beta-HSD type 1) inhibitorsand DPP-IV inhibitors (e.g. sitagliptin, vildagliptin, alogliptin,linagliptin and saxagliptin).

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment or prevention of diseases or conditions which may beaffected or which are mediated by the inhibition of the acetyl-CoAcarboxylase(s), in particular ACC2, in particular diseases or conditionsas described hereinbefore and hereinafter.

In yet another aspect the present invention relates a method fortreating, including preventing a disease or condition mediated by theinhibition of acetyl-CoA carboxylase(s) in a patient that includes thestep of administering to the patient, preferably a human, in need ofsuch treatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter,

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Further aspects of the invention include the use of a compound accordingto the invention or a salt thereof as a crop protection agent to combatand/or prevent fungal infestations, or to control other pests such asweeds, insects, or acarids that are harmful to crops. Another aspect ofthe invention relates to the use of a compound according to theinvention or a salt thereof for controlling and/or preventing plantpathogenic microorganisms, for example plant pathogenic fungi. Thereforeone aspect of the invention is a compound according to the formula (I)or a salt thereof for use as a fungicide, insecticide, acaricide and/orherbicide. Another aspect of the invention relates to an agriculturalcomposition comprising a compound of the present invention together withone or more suitable carriers. Another aspect of the invention relatesto an agricultural composition comprising a compound of the presentinvention in combination with at least one additional fungicide and/orsystemically acquired resistance inducer together with one or moresuitable carriers.

EXAMPLES

The Examples that follow are intended to illustrate the presentinvention without restricting it. The terms “ambient temperature” and“room temperature” are used interchangeably and designate a temperatureof about 20° C.

Preliminary Remarks:

As a rule, 1H-NMR and/or mass spectra have been obtained for thecompounds prepared. The R_(f) values are determined using Merck silicagel 60 F₂₅₄ plates and UV light at 254 nm.

Experimental Part

The following abbreviations are used above and hereinafter:

aq. aqueous ACN acetonitrile BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene CDI N,N-carbonyldiimidazole CDT N,N-carbonylditriazole DBU1,8-diazabicycloundec-7-ene DCM dichloromethane DIPEAN,N-diisopropylethylamine DMF N,N-dimethylformamide dppf1,1′-bis[diphenylphosphino]-ferrocene EtOAc ethyl acetate FA formic acidHATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HOBt N-Hydroxybenzotriazole MeOH methanol n.d. notdetermined PE petroleum ether rt room temperature (about 20° C.) sat.saturated TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuranTBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluroniumtetrafluoroboratAnalytic Methods1) HPLCMethod A

Analytical Column: XBridge C18, 3 × 30 mm, 2.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% TFA] [methanol] [mL/min] [° C.]0.0 95 5 2.2 60 0.30 95 5 2.2 60 1.50 0 100 2.2 60 1.55 0 100 2.9 601.70 0 100 2.9 60Method B

time Vol % water Vol % methanol (min) (incl. 0.2% NH₄OH) (incl. 3%water) 0.0 95 5 0.2 95 5 2.2 5 95 2.3 5 95 2.4 0 100 2.6 0 100

Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; columntemperature: 60° C.; flow: 1.3 mL/min.

Method C

time Vol % water Vol % methanol (min) (incl. 0.2% NH₄OH) (incl. 3%water) 0.0 95 5 0.2 95 5 2.2 5 95 2.3 5 95 2.4 0 100 2.6 0 100

Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; columntemperature: 40° C.; flow: 1.3 mL/min.

Method D

time Vol % (min) 0.01M NH₄OAc Vol % ACN 0.0 90 10 8.0 10 90 15.0 10 9015.1 90 10

Analytical column: XBridge C8 (Waters) 5.0 μm; 4.6×150 mm; columntemperature: rt; flow: 1.0 mL/min.

Method E

time Vol % (min) 0.01M NH₄OAc Vol % ACN 0.0 70 30 8.0 10 90 15.0 10 9015.1 70 30

Analytical column: XBridge C8 (Waters) 5.0 μm; 4.6×150 mm; columntemperature: rt; flow: 1.0 mL/min.

Method F

time Vol % water (min) (incl. 0.05% TFA) Vol % ACN 0.0 70 30 8.0 10 9015.0 10 90 15.1 70 30

Analytical column: Kromasil C18 5.0 μm; 4.6×250 mm; column temperature:rt; flow: 1.0 mL/min.

Method G

Vol % time Vol % water acetonitrile (min) (incl. 0.1% FA) (incl. 0.1%FA) 0.0 95 5 0.1 95 5 3.1 2 98 4.5 2 98 5.0 95 5

Analytical column: X-terra MS C18 (Waters) 2.5 μm; 4.6×30 mm; columntemperature: rt; flow: 1.0 mL/min.

Method H

Analytical Column: Venusil XBP-C18, 2.1 × 50 mm, 5 μm (Agela) Vol % Vol% time [H₂O, [ACN, Flow Temperature [min] 0.0375% TFA] 0.018% TFA][mL/min] [° C.] 0.0 90 10 1 50 2.00 20 80 1 50 2.48 20 80 1 50 2.50 9010 1 50 3.00 90 10 1 50Method I

Analytical Column: Venusil MP-C18, 4.6 × 50 mm, 5 μm (Agela) Vol % Vol %time [H₂O, [ACN, Flow Temperature [min] 0.0675% TFA] 0.625% TFA][mL/min] [° C.] 0.0 100 0 1 40 4.00 40 60 1 40 5.20 40 60 1 40 5.21 1000 1 40 7.00 100 0 1 40Method J

Analytical Column XBridge C18, 2.1 × 50 mm, 3.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [ACN, 0.1% FA] [H₂O, 0.1% FA] [mL/min] [°C.] 0.0 5 95 0.8 35 3.50 98 2 0.8 35 6.00 98 2 0.8 35Method K

Analytical Column XBridge C18, 3 × 30 mm, 2.5 μm (Waters) time Vol % Vol% Flow Temperature [min] [H₂O, 0.2% NH₄OH] [methanol] [mL/min] [° C.]0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100 2.2 60Method L

time Vol % water (min) (incl. 0.05% TFA) Vol % ACN 0.0 70 30 8.0 10 9015.0 10 90 15.1 70 30

Analytical column: XBridge C18 (Waters) 3.5 μm; 4.6×150 mm; columntemperature: rt; flow: 1.0 mL/min.

Method M

Analytical Column: XBridge C18, 4.6 × 50 mm, 3.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% NH₄OH] [methanol] [mL/min] [°C.] 0.0 80 20 2.0 60 1.7 0 100 2.0 60 2.5 0 100 2.0 60 2.6 80 20 2.0 60Method N

Analytical Column: XBridge C18, 3 × 30 mm, 2.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% NH₄OH] [methanol] [mL/min] [°C.] 0.0 95 5 2.2 60 0.30 95 5 2.2 60 1.50 0 100 2.2 60 1.55 0 100 2.9 601.70 0 100 2.9 60Method O

Analytical Column: Ascentis Express C18, 2.1 × 50 mm, 2.7 μm time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% TFA] [ACN] [mL/min] [° C.] 0.095 5 1.5 60 0.7 1 99 1.5 60 0.8 1 99 1.5 60 0.81 95 5 1.5 60Method P

Analytical Column: Sunfire C18, 4.6 × 50 mm, 3.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% TFA] [methanol] [mL/min] [° C.]0.0 80 20 2.0 60 1.7 0 100 2.0 60 2.5 0 100 2.0 60 2.6 80 20 2.0 60Method Q

Analytical Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% TFA] [methanol] [mL/min] [° C.]0.00 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100 2.2 60Method R

Analytical Column: XBridge C18, 4.6 × 30 mm, 2.5 μm (Waters) time Vol %Vol % Flow Temperature [min] [H₂O, 0.1% TFA] [methanol] [mL/min] [° C.]0.00 95 5 4.0 60 0.05 95 5 3.0 60 2.05 0 100 3.0 60 2.10 0 100 4.5 602.40 0 100 4.5 60Method S

Analytical Column: Stable Bond C18, 3.0 × 30 mm, 1.8 μm (Waters) timeVol % Vol % Flow Temperature [min] [H₂O, 0.1% TFA] [methanol] [mL/min][° C.] 0.00 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 1002.2 60

Preparation of Starting Compounds Example I Example I.11-Bromo-4-cyclobutoxybenzene

2.50 g (14.5 mmol) 4-bromophenol, 2.05 mL (21.7 mmol) cyclobutylbromideand 7.99 g (57.8 mmol) K₂CO₃ are dissolved in 25 mL DMF and stirred at120° C. for 12 h. Afterwards the reaction mixture is diluted with waterand extracted with EtOAc. The organic layer is dried over MgSO₄ and thesolvent is removed in vacuo. The crude product is used without furtherpurification.

C₁₀H₁₁BrO (M=227.1 g/mol)

ESI-MS: 227 [M+H]⁺

R_(t) (HPLC): 1.39 min (method A)

The following compounds are prepared analogously to example I.1:

R_(t)(HPLC) ESI-MS [min] Ex. Starting material Reagent Product structure[m/z] (method) I.1 

cyclobutyl- bromide

227 [M + H]⁺ 1.39 (A) I.2 

ethyl- bromide

231 [M + H]⁺ 2.00 (C) I.3 

244/246 [M]⁺ 2.08 (B) I.4 

cyclobutyl- chloride

n.d. 8.79 (E) I.5*

n-propyl- bromide

n.d. 2.31 (C) *R_(f) (TLC): 0.79 (silica gel, cyclohexane/EtOAc 9:1)

Example II Example II.1 4-(4-Ethoxy-phenyl)-piperidine

a) 4-(4-Ethoxy-phenyl)-pyridine

Under inert gas atmosphere 88 mg (0.12 mmol) PdCl₂(dppf)_(x)CH₂Cl₂, 13.6mL (27.2 mmol) 2N sodium carbonate solution and 1.64 g (13.3 mmol)pyridine-4-boronic acid are added to 3.00 g (12.1 mmol)1-ethoxy-4-iodo-benzene in 18 mL 1,4-dioxane and 6 mL methanol. Themixture is stirred for 2 d at reflux. After that time, water is added.The precipitate is filtered off, taken up in DCM and extracted withwater. The organic layer is dried over sodium sulphate and the solventis evaporated. The residue is purified by column chromatography (silicagel; gradient DCM:MeOH 100:0→95:5) to yield the desired product which isdirectly used in the next reaction step.

b) 4-(4-Ethoxy-phenyl)-piperidine

410 mg (2.06 mmol) 4-(4-Ethoxy-phenyl)-pyridine in 10 mL acetic acid arehydrogenated (3 bar) for 9 h at rt using 50 mg platinum(IV) oxide. Afterthat time, the catalyst is filtered off and the solvent is evaporated.The residue is taken up in 1N NaOH and extracted with EtOAc. The organiclayer is dried over sodium sulphate and the solvent is evaporated. Theresidue is purified by column chromatography (silica gel; DCM:MeOH 9:1,then THF:MeOH:NH₄OH 1:1:0.1) to yield the desired product.

C₁₃H₁₉NO (M=205.3 g/mol)

ESI-MS: 206 [M+H]⁺

R_(t) (HPLC): 1.86 min (method C)

The following compounds are prepared analogously to example 11.1:

R_(t)(HPLC) EI-MS [min] Example Starting material Product structure[m/z] (method) II.1 

206 [M + H]⁺ 1.86 (C) II.2 

250 [M + H]⁺ 6.37 (D) II.3 

220 [M + H]⁺ 6.12 (D) II.4 

232 [M + H]⁺ 3.82 (L) II.5 

232 [M + H]⁺ 3.84 (L) II.6 

220 [M + H]⁺ 3.90 (E) II.7 

206 [M + H]⁺ 1.31 (A) II.8 

232 [M + H]⁺ 4.32 (E) II.9 

234 [M + H]⁺ 6.51 (D) II.10

220 [M + H]⁺ 5.27 (F) II.11

220 [M + H]⁺ 1.25 (A) II.12

206 [M + H]⁺ 1.18 (A) II.13

236 [M + H]⁺ 2.32 (H)

Example III Example III.1 (S)—N-[1-(4-Bromo-phenyl)-ethyl]-acetamide

23.6 mL (250 mmol) acetic anhydride are added to 50.0 g (250 mmol)(S)-1-(4-bromophenyl)-ethylamine in 200 mL DCM while keeping thereaction temperature below 30° C. Stirring is continued for 12 h at rt.After that time, saturated NaHCO₃-solution is added. The organic layeris separated, washed with water, dried over magnesium sulphate and thesolvent is removed by evaporation.

C₁₀H₁₂BrNO (M=242.1 g/mol), ESI-MS: 242 [M+H]⁺

R_(t) (HPLC): 1.03 min (method N)

The following compounds are prepared analogously to Example III.1:

Example III.2 N-[2-(4-Bromo-phenyl)-1-methyl-ethyl]-acetamide

Educt: 2-(4-Bromo-phenyl)-1-methyl-ethylamine (J. Org. Chem. 1985, 50,133).

C₁₁H₁₄BrNO (M=256.1 g/mol), ESI-MS: 256 [M+H]⁺

R_(t) (HPLC): 2.60 min (method G)

Example III.3 (S)-Cyclopropanecarboxylic acid[1-(4-bromo-phenyl)-ethyl]amide

C₁₂H₁₄BrNO (M=268.2 g/mol), ESI-MS: 268 [M+H]⁺

R_(t) (HPLC): 2.76 min (method G)

Example III.4 N-[3-(4-Bromo-phenyl)-1-methyl-propyl]-acetamide

Educt: 3-(4-Bromo-phenyl)-1-methyl-propylamine

C₁₂H₁₆BrNO (M=270.2 g/mol), ESI-MS: 270 [M+H]⁺

R_(t) (HPLC): 2.11 min (method C)

Example IV Example IV.14-[4-(2,2-Difluoro-cyclopropylmethoxy)-phenyl]-piperidine hydrochloride

4.48 g (19.2 mmol, 80%) Methanesulfonic acid2,2-difluoro-cyclopropylmethyl ester are added to 5.93 g (19.2 mmol,90%) 4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl esterand 5.36 g (38.5 mmol) K₂CO₃ in 60 mL DMF. Stirring is continued for 12h at 50° C. under inert gas atmosphere. After that time, brine (50 mL)is added and the mixture is extracted with EtOAc (3×50 mL). The organiclayer is separated, washed with brine, dried over sodium sulphate andthe solvent is removed by evaporation. The residue is purified by columnchromatography (silica gel; gradient PE:EtOAc 20:1→10:1). The residue istaken up in 20 mL DCM and 100 mL 4N HCl in EtOAc are added dropwise at0° C. The mixture is stirred for 12 h at rt. After that time, thesolvent is removed in vacuo to yield the desired product.

C₁₅H₁₉F₂NO (M=267.3 g/mol), EI-MS: 267 [M]⁺

R_(t) (HPLC): 3.34 min (method I)

Example V Example V.1 (S)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acidmethyl ester

17.2 g (105 mmol) CDT are added to a mixture of 20.0 g (100 mmol)(S)-1-(4-bromophenyl)-ethylamine and 17.6 mL (125 mmol) TEA in 300 mLdichloromethane at 0° C. Stirring is continued for 15 min at 5° C. Afterthat time, the solvent is removed in vacuo and taken up in 50 mLmethanol. 33.4 mL (180 mmol) sodium methoxide in methanol (30%) areadded and stirring is continued for 48 h at rt. After that time, thesolvent is removed in vacuo, the residue is taken up in ethyl acetateand washed with sat. KHSO₄-solution (2×) and water. The organic layer isdried over magnesium sulphate and the solvent is removed by evaporation.

C₁₀H₁₂BrNO₂ (M=258.1 g/mol), ESI-MS: 258 [M+H]⁺

R_(t) (HPLC): 2.60 min (method B)

The following compounds are prepared analogously to Example V.1:

Example V.2 (S)-3-[1-(4-Bromo-phenyl)-ethyl]-1,1-dimethyl-urea

Educt: dimethylamine

C₁₁H₁₅BrN₂O (M=271.2 g/mol), ESI-MS: 271 [M+H]⁺

R_(t) (HPLC): 1.68 min (method B)

Example VI Example VI.16-Ethoxy-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

Under inert gas atmosphere 5.00 g (23.3 mmol) 5-bromo-2-ethoxy-pyridineare added to a mixture of 7.19 g (23.3 mmol)4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester, 95 mg (1.2 mmol) PdCl₂(dppf)_(x)CH₂Cl₂ and 15.2 g(46.5 mol) Cs₂CO₃ in 50 mL DMF and 10 mL H₂O. The mixture is stirred for12 h at 80° C. After that time, the solvent is evaporated, the residuetaken up in DCM and washed with brine. After drying over sodiumsulphate, the solvent is removed in vacuo and the residue is purified bycolumn chromatography (silica gel; gradient PE/EtOAc 20:1→10:1) to yieldthe desired product which was directly used in the next step.

C₁₇H₂₄N₂O₃ (M=304.4 g/mol)

R_(f) (TLC): 0.30 (silica gel, PE/ethyl acetate 20:1)

The following compounds are prepared analogously to Example VI.1:

Example VI.2 2′-Ethoxy-3,6-dihydro-2H-[4,4′]bipyridinyl-1-carboxylicacid tert-butyl ester

Educt: 4-bromo-2-ethoxy-pyridine

C₁₇H₂₄N₂O₃ (M=304.4 g/mol)

R_(f) (TLC): 0.30 (silica gel, PE/ethyl acetate 20:1)

Example VII Example VII.16-Ethoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

5.80 g (17.9 mmol)6-Ethoxy-3,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (VI.1) in 60 mL ethanol are hydrogenated (40 psi) for12 h at rt using 500 mg palladium on charcoal (10%). After that time,the catalyst is filtered off and the solvent is evaporated. The residueis purified by column chromatography (silica gel; gradient PE/EtOAc20:1→10:1) to yield the desired product which is directly used in thenext step.

C₁₇H₂₆N₂O₃ (M=306.4 g/mol)

R_(f) (TLC): 0.20 (silica gel, PE/ethyl acetate 20:1)

The following compounds are prepared analogously to Example VII.1:

Example VII.22′-Ethoxy-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acidtert-butyl ester

Educt: VI.2

C₁₇H₂₆N₂O₃ (M=306.4 g/mol)

R_(f) (TLC): 0.20 (silica gel, PE/ethyl acetate 20:1)

Example VIII Example VIII.16-Ethoxy-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl hydrochloride

To 4.30 g (13.9 mmol)6-Ethoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester (VII.1) in 10 mL EtOAc are added 120 mL 4N HCl inEtOAc. The mixture is stirred for 12 h at rt. After that time, thesolvent is evaporated to yield the desired product.

C₁₂H₁₈N₂O*HCl (M=242.7 g/mol)

R_(f) (TLC): 0.10 (silica gel, DCM/methanol 10:1)

The following compounds are prepared analogously to Example VIII.1:

Example VIII.2 2′-Ethoxy-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl

Educt: VII.2

C₁₂H₁₈N₂O*HCl (M=242.7 g/mol)

R_(f) (TLC): 0.10 (silica gel, DCM/methanol 10:1)

Example IX Example IX.1 2-Methyl-propane-2-sulfonic acid4-bromo-3-fluoro-benzylideneamide

11.1 g (91.0 mmol) 2-Methyl-2-propanesulfinamide are added to 16.5 g(76.0 mmol) 4-bromo-3-fluoro-benzaldehyde and 34.6 g (152 mmol)titanium(IV) ethoxide in 100 mL THF. Stirring is continued for 1.5 h at50° C. After that time, the mixture is poured into brine. The mixture isfiltered over celite and the filtrate is transferred to a separationfunnel. The organic layer is separated, dried over magnesium sulphateand the solvent is removed by evaporation. The residue is purified bycolumn chromatography (silica gel; gradient hexane/EtOAc 1:0→3:2) toyield the desired product.

C₁₁H₁₃BrFNOS (M=306.2 g/mol), ESI-MS: 306/308 [M+H]⁺

R_(f) (TLC): 0.30 (silica gel, hexane/EtOAc 4:1)

The following compounds are prepared analogously to Example IX.1:

Example IX.2 2-Methyl-propane-2-sulfonic acid4-bromo-2-fluoro-benzylideneamide

Educt: 4-bromo-2-fluoro-benzaldehyde

C₁₁H₁₃BrFNOS (M=306.2 g/mol), ESI-MS: 306/308 [M+H]⁺

Example IX.3 2-Methyl-propane-2-sulfonic acid4-bromo-3-methoxy-benzylideneamide

Educt: 4-bromo-3-methoxy-benzaldehyde

C₁₂H₁₆BrNO₂S (M=318.2 g/mol), ESI-MS: 318/320 [M+H]⁺

R_(f) (TLC): 0.60 (silica gel, hexane/EtOAc 2:1)

Example X Example X.1 2-Methyl-propane-2-sulfonic acid[1-(4-bromo-3-fluoro-phenyl)-ethyl]amide

Under inert gas atmosphere 37.2 mL (112 mmol) of a 3N solution of methylmagnesium bromide in THF are added dropwise to 17.1 g (55.8 mmol)2-methyl-propane-2-sulfonic acid 4-bromo-3-fluoro-benzylideneamide(IX.1) in 170 mL THF at −78° C. The cooling bath is removed and stirringis continued for 2 h. After that time, the mixture is poured into sat.NH₄Cl-solution (300 mL) and extracted with EtOAc. The organic layer isseparated, washed with brine and dried over sodium sulphate. The solventis removed by evaporation to yield the desired product.

C₁₂H₁₇BrFNOS (M=322.2 g/mol), ESI-MS: 322/324 [M+H]⁺

The following compounds are prepared analogously to Example X.1:

Example X.2 2-Methyl-propane-2-sulfonic acid[1-(4-bromo-2-fluoro-phenyl)-ethyl]amide

Educt: IX.2

C₁₂H₁₇BrFNOS (M=322.2 g/mol), ESI-MS: 322/324 [M+H]⁺

Example X.3 2-Methyl-propane-2-sulfonic acid[1-(4-bromo-3-methoxy-phenyl)-ethyl]amide

Educt: IX.3

C₁₃H₂₀BrNO₂S (M=334.3 g/mol), ESI-MS: 334/336 [M+H]⁺

Example XI Example XI.1 N-[1-(4-Bromo-3-fluoro-phenyl)-ethyl]acetamide

20.0 mL 4N HCl in dioxane are added to 17.2 g (53.4 mmol)2-methyl-propane-2-sulfonic acid[1-(4-bromo-3-fluoro-phenyl)-ethyl]-amide (X.1) in 150 mL MeOH. Stirringis continued for 1 h. After that time, the mixture is concentrated andthe residue is triturated from diethylether (150 mL). The precipitate isfiltered off, washed with diethylether and suspended in 250 mL DCM. 8.64mL (107 mmol) pyridine and 5.29 mL (56.1 mmol) acetic anhydride areadded and the mixture is stirred for 12 h at rt. After that time, themixture is transferred to a separation funnel, washed with 1N HCl (200mL) and sat. aq. NaHCO3-solution (200 mL) and dried over sodiumsulphate. The solvent is removed by evaporation to yield the desiredproduct.

C₁₀H₁₁BrFNO (M=260.1 g/mol), ESI-MS: 260/262 [M+H]⁺

R_(t) (HPLC): 2.60 min (method J)

The following compounds are prepared analogously to Example XI.1:

Example XI.2 N-[1-(4-Bromo-2-fluoro-phenyl)-ethyl]acetamide

Educt: X.2

C₁₀H₁₁BrFNO (M=260.1 g/mol), ESI-MS: 260/262 [M+H]⁺

R_(t) (HPLC): 2.60 min (method J)

Example XI.3 N-[1-(4-Bromo-3-methoxy-phenyl)-ethyl]acetamide

Educt: X.3

C₁₁H₁₄BrNO₂ (M=272.1 g/mol), ESI-MS: 272/274 [M+H]⁺

R_(t) (HPLC): 2.56 min (method J)

Example XII Example XII.1(S)-1-{4-[4-(4-Ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylaminehydrochloride

Under inert gas atmosphere 19.47 g (94.86 mmol)4-(4-ethoxy-phenyl)-piperidine (II.1) are added to a mixture of 29.9 g(99.6 mmol) (S)-1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butylester, 36.5 g (0.38 mol) sodium tert-butyrat, 17.35 g (18.97 mmol)tris-(dibenzylidenaceton)-dipalladium(0) and 14.15 g (47.43 mmol)2-(di-tert-butylphosphino)biphenyl in 750 mL 1,4-dioxane. The mixture isstirred for 6 h at 50° C. and for additional 5 h at 55° C. After thattime, additional 5.00 g (5.47 mmol)tris-(dibenzylidenaceton)-dipalladium(0) and 5.00 g (16.8 mmol)2-(di-tert-butyl-phosphino)biphenyl in 750 mL 1,4-dioxane are added andstirring is continued for 4 h at 55° C. Finally the mixture is filteredover Celite, the residue washed with ACN (500 mL) and the combinedsolvent evaporated. The residue is purified by column chromatography(silica gel, 15-50% EtOAc in heptanes). The product is taken up ini-propanol (50 mL) and 100 mL 5-6 N HCl in i-propanol are added. Themixture is stirred for 4 h at rt. After that time, the mixture isconcentrated. The residue is triturated with diethylether to yield thedesired product.

C₂₁H₂₈N₂O.HCl (M=360.9 g/mol), ESI-MS: 325 [M+H]⁺

R_(t) (HPLC): 0.88 min (method Q)

Preparation of Final Compounds Example 1 Example 1.1(S)—N-(1-{4-[4-(4-Propoxy-phenyl)-piperidin-1-yl]-phenyl}-ethyl)-acetamide

80 mg (0.37 mmol) 4-(4-Propoxy-phenyl)-piperidine (II.3) are added to amixture of 88 mg (0.37 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide(III.1), 145 mg (97%, 1.46 mmol) sodium tert-butyrat, 44 mg (0.15 mmol)2-(di-tert-butylphosphino)biphenyl and 33 mg (0.036 mmol)tris-(dibenzylidenaceton)-dipalladium(0) in 2.0 mL 1,4-dioxane. Themixture is stirred for 12 h at 70° C. After that time, the mixture isfiltered over celite, the solvent is removed in vacuo and the residue ispurified by HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3%NH₄OH, eluent B: MeOH) to yield the desired product.

C₂₄H₃₂N₂O₂ (M=380.5 g/mol)

ESI-MS: 381 [M+H]⁺

R_(t) (HPLC): 1.29 min (method K)

The following compounds of general formula (I-1) are preparedanalogously to Example 1.1, the educts used being shown in the columnheaded “E 1” and “E 2”. Alternatively heating at reaction temperaturesof 20-120° C. with or without microwave irradiation is used in theexamples below:

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 1.1 

*—CH₃ II.3 III.1 381 [M + H]⁺ 1.29 (K) 1.2 

*—CH₃ II.1 III.1 367 [M + H]⁺ 1.18 (K) 1.3 

*—CH₃ II.9 III.1 395 [M + H]⁺ 1.30 (K) 1.4 

*—CH₃ II.8 III.1 393 [M + H]⁺ 1.30 (K) 1.5 

*—CH₃ II.5 III.1 393 [M + H]⁺ 1.26 (K) 1.6 

*—CH₃ II.12 III.1 367 [M + H]⁺ 1.21 (K) 1.7 

*—CH₃ IV.1 III.1 429 [M + H]⁺ 1.34 (A) 1.8 

II.1 III.3 393 [M + H]⁺ 1.22 (K) 1.9 

II.6 V.2 410 [M + H]⁺ 1.26 (K) 1.10

II.6 III.3 407 [M + H]⁺ 1.28 (K) 1.11

*—CH₃ II.13 III.1 397 [M + H]⁺ 1.35 (A) 1.12

*—CH₃ VIII.1 III.1 368 [M + H]⁺ 1.25 (A) 1.13

*—CH₃ II.2 III.1 412 [M + H]⁺ 1.28 (K) 1.14

*—CH₃ II.7 III.1 393 [M + H]⁺ 1.29 (K) 1.15

II.4 III.3 419 [M + H]⁺ 1.30 (K) 1.16

II.8 III.3 419 [M + H]⁺ 1.33 (K) 1.17

II.1 V.2 396 [M + H]⁺ 1.34 (K) 1.18

*—CH₃ II.6 III.1 381 [M + H]⁺ 1.30 (K) 1.19

*—CH₃ VIII.2 III.1 368 [M + H]⁺ 1.25 (A) 1.20

*—CH₃ II.10 III.1 381 [M + H]⁺ 1.28 (K) 1.21

II.3 III.3 407 [M + H]⁺ 1.32 (K) 1.22

II.8 V.2 422 [M + H]⁺ 1.31 (K) 1.23

*—CH₃ II.4 III.1 393 [M + H]⁺ 1.26 (K) 1.24

II.4 V.2 422 [M + H]⁺ 1.30 (K) 1.25

*—CH₃ II.11 III.1 381 [M + H]⁺ 1.36 (K) 1.26

II.3 V.2 410 [M + H]⁺ 1.30 (K) 1.27

*—CH₃ 4-(4- methoxy- phenyl)- piperidine III.1 353 [M + H]⁺ 0.89 (S)

The following compounds of general formula (I-2) are preparedanalogously to Example 1.1, the educts used being shown in the columnheaded “E 1” and “E 2”. Alternatively heating at reaction temperaturesof 20-120° C. with or without microwave irradiation is used in theexamples below:

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 1.30

*—CH₃ II.9 XI.1 413 [M + H]⁺ 1.44 (A) 1.31

*—CH₃ II.2 XI.1 429 [M + H]⁺ 1.43 (A) 1.32

*—CH₃ II.3 XI.1 399 [M + H]⁺ 1.42 (A) 1.33

*—CH₃ II.6 XI.1 399 [M + H]⁺ 1.39 (A)

The following compounds of general formula (I-3) are preparedanalogously to Example 1.1, the educts used being shown in the columnheaded “E 1” and “E 2”. Alternatively heating at reaction temperaturesof 20-120° C. with or without microwave irradiation is used in theexamples below:

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 1.40

*—CH₃ II.3 XI.2 399 [M + H]⁺ 1.41 (A) 1.41

*—CH₃ II.12 XI.2 385 [M + H]⁺ 1.36 (A) 1.42

*—CH₃ II.11 XI.2 399 [M + H]⁺ 1.39 (A) 1.43

*—CH₃ II.8 XI.2 411 [M + H]⁺ 1.42 (A) 1.44

*—CH₃ II.9 XI.2 413 [M + H]⁺ 1.44 (A) 1.45

*—CH₃ II.1 XI.2 385 [M + H]⁺ 1.36 (A) 1.46

*—CH₃ II.6 XI.2 399 [M + H]⁺ 1.38 (A) 1.47

*—CH₃ II.7 XI.2 411 [M + H]⁺ 1.42 (A) 1.48

*—CH₃ II.2 XI.2 429 [M + H]⁺ 1.42 (A)

The following compounds of general formula (I-4) are preparedanalogously to Example 1.1, the educts used being shown in the columnheaded “E 1” and “E 2”. Alternatively heating at reaction temperaturesof 20-120° C. with or without microwave irradiation is used in theexamples below:

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 1.50

*—CH₃ II.9 XI.3 425 [M + H]⁺ 1.43 (A) 1.51

*—CH₃ II.8 XI.3 423 [M + H]⁺ 1.42 (A) 1.52

*—CH₃ II.3 XI.3 411 [M + H]⁺ 1.41 (A)

The following compounds of general formula (I-5) are preparedanalogously to Example 1.1, the educts used being shown in the columnheaded “E 1” and “E 2”. Alternatively heating at reaction temperaturesof 20-120° C. with or without microwave irradiation is used in theexamples below and BINAP/toluene is used instead of2-(di-tert-butylphosphino)biphenyl/dioxane in example 1.61:

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 1.60

*—CH₃ II.1 III.2 381 [M + H]⁺ 2.20 (C) 1.61

*—CH₃ 4-(4- methoxy- phenyl)- piperidine III.2 367 [M + H]⁺ 2.16 (G)

The following compounds of general formula (I-6) are preparedanalogously to Example 1.1, the educts used being shown in the columnheaded “E 1” and “E 2”. Alternatively heating at reaction temperaturesof 20-120° C. with or without microwave irradiation is used in theexamples below:

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 1.70

*—CH₃ II.1 III.4 395 [M + H]⁺ 2.25 (C)

Example 2 Example 2.1 (S)-1-Cyano-cyclopropanecarboxylic acid(1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethyl)-amide

To a mixture of 14 mg (0.13 mmol) 1-cyano-cyclopropanecarboxylic acid in1 mL DMF are added 52 μL (0.30 mmol) DIPEA and 49 mg (0.13 mmol) HATU.The mixture is stirred for 10 min at rt. Subsequently a mixture of 36 mg(0.10 mmol)(S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylaminehydrochloride (XII.1) in 1 mL DMF is added and stirring is continued for6 h at rt. The crude mixture is directly purified by HPLC (Sunfire,narrow gradients, water (+0.1% TFA)/methanol) to yield the desiredproduct.

C₂₆H₃₁N₃O₂ (M=417.6 g/mol), ESI-MS: 418 [M+H]⁺

R_(t) (HPLC): 1.92 min (method M)

The following compounds of general formula (2-1) are preparedanalogously to Example 2.1, the educts used being shown in the columnheaded “E 1” and “E 2”.

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 2.1

XII.1

418 [M + H]⁺ 1.92 (M) 2.2

XII.1

436 [M + H]⁺ 1.88 (M) 2.3

XII.1

413 [M + H]⁺ 1.90 (M) 2.4

XII.1

381 [M + H]⁺ 1.88 (M) 2.5

XII.2

397 [M + H]⁺ 1.90 (M) 2.6

XII.1

421 [M + H]⁺ 1.93 (M) 2.7

XII.1

407 [M + H]⁺ 1.94 (M)

Example 3 Example 3.1 (S)-2-Acetylamino-oxazole-4-carboxylic acid(1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethyl)-amide

To a mixture of 2.0 mg (0.012 mmol) 2-acetylamino-oxazole-4-carboxylicacid, 3.6 mg(S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylaminehydrochloride (XII.1) and 3.54 (0.02 mmol) DIPEA in 0.27 mL DMF areadded 3.9 mg (0.012 mmol) TBTU. The mixture is shaken at rt for 12 h. 25μl K₂CO₃ solution (3 M) is added, the mixture is filtered through basicalumina, washed with DMF/MeOH (9:1) and concentrated to yield thedesired product.

C₂₇H₂₂N₄O₄ (M=476.6 g/mol), ESI-MS: 477 [M+H]⁺

R_(t) (HPLC): 0.54 min (method O)

The following compounds of general formula (3-1) are preparedanalogously to Example 3.1, the educts used being shown in the columnheaded “E 1” and “E 2”.

R_(t) HPLC ESI-MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 3.1

XII.1

477 [M + H]⁺ 0.54 (O) 3.2

XII.1

403 [M + H]⁺ 0.53 (O) 3.3

XII.1

399 [M + H]⁺ 0.55 (O) 3.4

XII.1

432 [M + H]⁺ 0.55 (O) 3.5

XII.1

487 [M + H]⁺ 0.54 (O) 3.6

XII.1

507 [M + H]⁺ 0.54 (O) 3.7

XII.1

493 [M + H]⁺ 0.54 (O) 3.8

XII.1

385 [M + H]⁺ 0.54 (O) 3.9

XII.1

383 [M + H]⁺ 0.53 (O)

Example 4 Example 4.1(S)-3-(1-{4-[4-(4-Ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethyl)-1-ethyl-1-methyl-urea

To 36 mg (0.10 mmol)(S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylaminehydrochloride (XII.1) in 1.5 mL 1,4-dioxane are added 37 μL (0.25 mmol)DBU and 33 mg (0.20 mmol) CDT. The mixture is stirred for 5 min at rt.Subsequently 7.1 mg (0.12 mmol) ethyl-methyl-amine in 1.0 mL 1,4-dioxaneare added and stirring is continued for 12 h at rt. The solvent isremoved under reduced pressure, the residue is taken up in DMF andpurified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol)to yield the desired product.

C₂₇H₂₂N₄O₄ (M=409.6 g/mol), ESI-MS: 410 [M+H]⁺

R_(t) (HPLC): 1.36 min (method P)

The following compounds of general formula (4-1) are preparedanalogously to Example 4.1, the educts used being shown in the columnheaded “E 1” and “E 2”.

R_(t) ESI- HPLC MS [min] Ex. R¹—Ar¹ R³ E 1 E 2 [m/z] (method) 4.1

XII.1

410 [M + H]⁺ 1.36 (P) 4.2

XII.1

459 [M + H]⁺ 1.15 (P) 4.3

XII.1

438 [M + H]⁺ 1.30 (P) 4.4

XII.1

424 [M + H]⁺ 1.41 (P)

Example 5 Example 5.1(S)-(1-{4-[4-(4-Ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethyl)-carbamicacid methyl ester

To a mixture of 36.1 mg (0.10 mmol)(S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylaminehydrochloride (XII.1) and 42.7 μL (0.250 mmol) DIPEA in 2 mL THF areadded 11.64 (0.150 mmol) methyl chloroformate at 0° C. The mixture isstirred for 12 h at rt. The solvent is removed under reduced pressure,the residue is taken up in DMF and purified by HPLC (Sunfire, narrowgradients, water (+0.1% TFA)/methanol) to yield the desired product.

C₂₃H₃₀N₂O₃ (M=382.5 g/mol), ESI-MS: 383 [M+H]⁺

R_(t) (HPLC): 1.52 min (method R)

Example 6 Example 6.1(S)—N-(1-{4-[4-(4-Ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethyl)-N-methyl-acetamide

To 34.5 mg (1.36 mmol, 95%) NaH in 2.5 mL THF at 0° C. are added 50.0 mg(0.136 mmol) of Example 1.2. The mixture is stirred for 10 min at 0° C.before 17.1 μL (0.273 mmol) methyl iodide are added and the mixture isstirred at rt for 2 h. The reaction is quenched by the addition of waterand a sat. aq. NH₄Cl solution. The resulting mixture is extracted withDCM, the organic layers are combined and dried over MgSO₄. The solventis removed in vacuo and the residue is triturated with diethyl ether.

C₂₄H₃₂N₂O₂ (M=380.5 g/mol), ESI-MS: 381 [M+H]⁺

R_(t) (HPLC): 2.16 min (method B)

The invention claimed is:
 1. A compound of the formula I

wherein Ar¹ is selected from the group consisting of:

wherein the beforementioned phenylene group is optionally substitutedwith F, —CH₃ or —OCH₃; Ar² is phenylene optionally substituted with F or—OCH₃; L is selected from the group consisting of: straight-chainC₁₋₄-alkylene, which may optionally be substituted with one or twoC₁₋₃-alkyl groups; R¹ is selected from the group consisting of:C₁₋₄-alkyl-O—, C₃₋₄-cycloalkyl-O— and C₃₋₄-cycloalkyl-CH₂—O—, whereineach alkyl and cycloalkyl may be optionally substituted with one or twoF atoms; R² is selected from the group consisting of: H and C₁₋₃-alkyl;and R³ is selected from the group consisting of: C₁₋₃-alkyl,—O—(C₁₋₂-alkyl), C₃₋₅-cycloalkyl, R^(N1)R^(N2)N—, morpholinyl,heteroaryl and heteroaryl-CH₂—, wherein each alkyl may be optionallysubstituted with one to three F atoms or one CN, OH, —O—CH₃ and —S—CH₃,and wherein each cycloalkyl may be optionally substituted with one CN,OH, or —CH₃, and wherein each heteroaryl group is selected from thegroup consisting of pyrrolyl, imidazolyl, pyrazolyl, oxazoly, thiazolyl,benzimidazolyl and pyridinyl, and wherein each heteroaryl group may beoptionally substituted with one or more substituents independentlyselected from the group consisting of phenyl, —CH₃ and —NH—C(═O)—CH₃,and wherein R^(N1) is selected from the group consisting of H andC₁₋₃-alkyl, and wherein R^(N2) is selected from the group consisting ofH, C₁₋₃-alkyl and pyridinyl; or a tautomer or pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein Ar²is selected from the group consisting of:

wherein the asterisk to the left side of each group indicates the bondwhich is connected to the piperidine ring of the core structure of theformula (I), and the asterisk to the right side of each group indicatesthe bond which is connected to L.
 3. A compound according to claim 1,wherein group L is selected from the group consisting of: straight-chainC₁₋₃-alkylene, which may optionally be substituted with one methylgroup.
 4. A compound according to claim 3, wherein L is —CH(CH₃)—.
 5. Acompound according to claim 1, wherein R² is H or CH₃.
 6. A compoundaccording to claim 5, wherein R² is H.
 7. A compound according to claim1, wherein R¹ is selected from the group consisting of: C₁₋₄-alkyl-O—,C₃₋₆-cycloalkyl-O— and C₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—, wherein each alkyland cycloalkyl may be optionally substituted with one or more F atoms.8. A compound according to claim 1, wherein R³ is selected from thegroup consisting of: C₁₋₃-alkyl, —O—CH₃, cyclopropyl, R^(N1)R^(N2)N—,morpholinyl, heteroaryl and heteroaryl-CH₂—, wherein each alkyl may beoptionally substituted with one to three F atoms or one CN, OH, —O—CH₃and —S—CH₃, and wherein each cycloalkyl may be optionally substitutedwith one CN, or —CH₃, and wherein each heteroaryl group is selected fromthe group consisting of pyrrolyl, pyrazolyl, oxazolyl, thiazolyl andpyridinyl, and wherein each heteroaryl group may be optionallysubstituted with one or two substituents independently selected from thegroup consisting of —CH₃ and —NH—C(═O)—CH₃, and wherein R^(N1) isselected from the group consisting of H and C₁₋₂-alkyl, and whereinR^(N2) is selected from the group consisting of H, C₁₋₃-alkyl andpyridinyl.
 9. A compound according to claim 8, wherein R³ is selectedfrom the group consisting of: C₁₋₃-alkyl, —CH₂F, —CHF₂, —CF₃, —CHF—CH₃,—CH₂—OH, —CH₂—OCH₃, —CH₂—S—CH₃, —OCH₃, —N(C₁₋₂-alkyl)₂,


10. A compound according to claim 9, wherein R³ is selected from thegroup consisting of: —CH₃, cyclopropyl and —N(CH₃)₂.
 11. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier or diluent.
 12. A method oftreating obesity or dyslipidemia in a patient suffering from one of saidconditions, which method comprises administering to said patient atherapeutically effective amount of a compound according to claim
 1. 13.A compound according to claim 1, wherein Ar² is selected from the groupconsisting of:

wherein the asterisk to the left side of each group indicates the bondwhich is connected to the piperidine ring of the core structure of theformula (I), and the asterisk to the right side of each group indicatesthe bond which is connected to L; L is selected from the groupconsisting of:

R¹ is selected from the group consisting of: C₁₋₄-alkyl-O—,C₃₋₄-cycloalkyl-O— and C₃₋₄-cycloalkyl-CH₂—O—, wherein each alkyl orcycloalkyl may be optionally substituted with one to three F atoms; R²is selected from the group consisting of: H; and R³ is selected from thegroup consisting of: C₁₋₃-alkyl, —O—CH₃, cyclopropyl, R^(N1)R^(N2)N—,morpholinyl, heteroaryl and heteroaryl-CH₂—, wherein each alkyl may beoptionally substituted with one to three F atoms or one CN, OH, —O—CH₃and —S—CH₃, and wherein each cycloalkyl may be optionally substitutedwith one CN, or —CH₃, and wherein each heteroaryl group is selected fromthe group consisting of pyrrolyl, pyrazolyl, oxazoly, thiazolyl andpyridinyl, and wherein each heteroaryl group may be optionallysubstituted with one or two substituents independently selected from thegroup consisting of —CH₃ and —NH—C(═O)—CH₃, and wherein R^(N1) isselected from the group consisting of H and C₁₋₂-alkyl, and whereinR^(N2) is selected from the group consisting of H, C₁₋₃-alkyl andpyridinyl; or a tautomer or pharmaceutically acceptable salt thereof.14. A compound according to claim 13, wherein R³ is selected from thegroup consisting of: —CH₃, cyclopropyl and —N(CH₃)₂.
 15. A compoundsaccording to claim 14, wherein Ar¹ and Ar² are each


16. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.